Early Neuromuscular Blockade in the Acute Respiratory ...Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome •4

2019/6/11慈恵ICU勉強会東京慈恵会医科⼤学附属柏病院救急部

阿部建彦

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med nejm.org 1

The members of the writing committee (Marc Moss, M.D., David T. Huang, M.D., M.P.H., Roy G. Brower, M.D., Niall D. Ferguson, M.D., Adit A. Ginde, M.D., M.P.H., M.N. Gong, M.D., Colin K. Gris-som, M.D., Stephanie Gundel, M.S., Douglas Hayden, Ph.D., R. Duncan Hite, M.D., Peter C. Hou, M.D., Catherine L. Hough, M.D., Theodore J. Iwashyna, M.D., Ph.D., Akram Khan, M.D., Kathleen D. Liu, M.D., Ph.D., Daniel Talmor, M.D., M.P.H., B. Taylor Thompson, M.D., Christine A. Ulysse, Ph.D., Donald M. Yealy, M.D., and Derek C. Angus, M.D., M.P.H.) as-sume responsibility for the overall con-tent and integrity of this article. The affili-ations of the members of the writing committee are listed in the Appendix. Address reprint requests to Dr. Angus at the University of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261, or at angusdc@ upmc . edu.

*A full list of the investigators in the Re-evaluation of Systemic Early Neuro-muscular Blockade (ROSE) trial and the Prevention and Early Treatment of Acute Lung Injury (PETAL) network is provided in the Supplementary Appen-dix, available at NEJM.org.

This article was published on May 19, 2019, at NEJM.org.

DOI: 10.1056/NEJMoa1901686Copyright © 2019 Massachusetts Medical Society.

BACKGROUNDThe benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear.

METHODSWe randomly assigned patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ≥8 cm of water) to a 48-hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical-ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in-hospital death from any cause at 90 days.

RESULTSThe trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, −0.3 percentage points; 95% confidence interval, −6.4 to 5.9; P = 0.93). While in the hospital, patients in the intervention group were less physi-cally active and had more adverse cardiovascular events than patients in the con-trol group. There were no consistent between-group differences in end points as-sessed at 3, 6, and 12 months.

CONCLUSIONSAmong patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets. (Funded by the National Heart, Lung, and Blood Institute; ROSE ClinicalTrials.gov number, NCT02509078.)

A BS TR AC T

Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome

The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network*

Original Article

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Copyright © 2019 Massachusetts Medical Society. All rights reserved.

N Engl J Med 2019; 380: 1997-2008PMID: 31112383

INTRODUCTION

集中治療領域では、“less intervention”が主流

• Lung-protective ventilation• Fewer transfusion• Less bed rest• Fewer intubation• Less sedation

ARDSに対するNMBの使⽤は、”Less is more”の精神に反する

N Engl J Med 2010;363: 1176-80.

Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome

• 4 ICUs in France, 56 patients• 2001.9-2001.12

• P/F <150• Cisatracurium 50mg bolus＋5mcg/kg/min 48hours• TOF 0になるように調整

• 120時間後の酸素化：NMB群で改善• ⼈⼯呼吸器期間・死亡率は有意差ないも、NMB群で良い傾向

Crit Care Med 2004; 32:113–119

Effects of NMBA on Oxygenation.When analyzed for the entire 120 hrs,there was a significant beneficial effect ofthe NMBA on the course of PaO2/FIO2 ra-tio (p ! .021 by two-way repeated-measures analysis of variance) as com-pared with the control group. Individualcomparisons at each time point indicatedthat patients randomized to NMBA had ahigher PaO2/FIO2 at 48, 96, and 120 hrsafter randomization (Fig. 1). Concerningshort-term effects, there was no modifi-cation of the PaO2/FIO2 ratio at 1 hr afterrandomization in the NMBA group (142" 46 vs. 130 " 34 at baseline, p ! .29)and in the control group (126 " 38 vs.119 " 31, p ! .48). The pharmacologicand nonpharmacologic treatments usedin these ARDS patients after inclusion aredetailed in Table 3. Prone positioning and

corticosteroids were never used duringthe first 5 days after inclusion.

Effects of NMBA on Requirements forFIO2 and PEEP. Repeated-measures anal-ysis of variance showed that PEEP de-creased during the 120-hr period in theNMBA group (p ! .036). Mean dailyPEEP values through day 5 are shown inFigure 2. A decrease of FIO2 over time wasobserved (p # .001) (Table 4).

Other Respiratory and HemodynamicEffects of NMBA. Peak and plateau pres-sures decreased over time (p ! .001 andp ! .012, respectively) (Tables 4 and 5).Two-way repeated-measures analysis ofvariance showed that this decrease overtime was reinforced in the group of pa-tients receiving NMBA (p ! .018 and p !.04, respectively). The evolution of pla-teau pressure is shown in Figure 3. The

present study showed that PaCO2 was notaffected by the use of NMBA. A slight butsignificant time-related increase of thepH was observed (p # .001). It was asso-ciated with a nonsignificant decrease ofPaCO2 and a nonsignificant increase ofHCO3 (data not shown). There was nodifference between the two groups con-cerning hemodynamic status.

Use of NMBA and Sedatives. All pa-tients included in the NMBA group pre-sented four responses to the train-of-fourassessment performed 8 hrs after the ter-mination of administration (48 hrs for allbut two patients; see below). Patients in-cluded in the NMBA group received 1324" 197 mg of cisatracurium. There was nodifference in temperature between thetwo groups throughout the study period(data not shown). One bolus of cisatra-curium was used in two patients includedin the control group for a sustained (5-min) increase of plateau pressure exceed-ing 35 cm H2O. Finally, only two patientsincluded in the NMBA group required acontinuous infusion of NMBA due to ahigh plateau pressure (for 24 and 48 hrslonger after the initial 48-hr period afterrandomization) group. Succinylcholinewas used in eight patients (five includedin the control group and three in theNMBA group) for a bronchoscopy per-formed in patients exhibiting a plateaupressure of 30–35 cm H2O (seven pa-tients) and a reintubation (one patient).

A Ramsay score of 6 was obtained inall patients included in the study duringthe first 48-hr period. Midazolam andsufentanil were used for longer periods inICU survivors included in the NMBAgroup than in ICU survivors included inthe control group, but the difference didnot reach statistical significance (Table2). The dosage of sufentanil and midazo-lam during the 120-hr period was notdifferent between the two groups (768 "372 mg of midazolam and 2840 " 1327$g of sufentanil for controls, 789 " 307mg of midazolam and 2687 " 1445 $g ofsufentanil in patients receiving NMBA).

Outcome. Only one patient from thecontrol group developed pneumothorax.No patient from the NMBA group pre-sented with barotrauma. No patient pre-sented clinically detectable critical illnessneuromyopathy. Thirteen patients in theNMBA group (46%) and 16 patients in thecontrol group (57%) presented with aventilator-associated pneumonia (not sig-nificant). As presented in Table 5, therewas no difference between the two groupsconcerning the duration of mechanical

Figure 1. Evolution of PaO2/FIO2 during the 120-hr period of the study. Results are expressed as mean" SEM. NMBA, neuromuscular blocking agents; *p # .001 vs. baseline by Tukey test.

Table 2. Hemodynamic and respiratory parameters at inclusion

NMBA Group(n ! 28)

Control Group(n ! 28) p Value

Norepinephrine, n (%) 18 (64) 22 (79) NSDobutamine, n (%) 8 (28.6) 5 (17.9) NSPulmonary artery catheter, n (%) 6 (21.4) 5 (17.9) NSHeart rate, beats/min 99 " 21 94 " 24 NSMAP, mm Hg 78 " 11 75 " 11 NSCVP, mm Hg 9.6 " 4.2 9.6 " 5.5 NSHemoglobin, g/L 93.8 " 17.7 101.5 " 19.6 NSPaO2/FIO2 130 " 34 119 " 31 NSPaCO2, torr 48.3 " 9.0 47.4 " 11.2 NSFIO2 70.2 " 17.0 67.3 " 15.8 NSPEEP, cm H2O 11.1 " 2.8 10.9 " 2.4 NSPEEPtot, cm H2O 12.3 " 3.0 11.4 " 2.5 NSTidal volume, mL/kg 7.1 " 1.1 7.4 " 1.9 NSPplat, cm H2O 27.1 " 6.2 26.1 " 4.0 NSPmean, cm H2O 17.7 " 3.3 17.2 " 2.7 NS

NMBA, neuromuscular blocking agent; NS, not significant; MAP, mean arterial pressure; CVP,central venous pressure; PEEP, positive end-expiratory pressure; PEEPtot, total PEEP; Pplat, plateaupressure; Pmean, mean pressure.

Values given as mean " SD unless otherwise noted.

115Crit Care Med 2004 Vol. 32, No. 1

Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome

ACURASYS• 20 ICUs in France, 340 pts.• 2006.3-2008.3

• P/F <150• Cisatracurium 15mg bolus＋37.5mg/hr 48hours

• 90⽇死亡率：31.6% vs. 40.7%• Barotrauma：5.1% vs. 11.7%

N Engl J Med 2010;363: 1176-80.

Neuromuscular Blocking Agents in ARDS

n engl j med 363;12 nejm.org september 16, 2010 1113

The incidence of ICU-acquired paresis, as evaluated on the basis of the MRC score on day 28 or at the time of ICU discharge, did not differ significantly between the two groups (Table 3).

Secondary Post Hoc OutcomeCorticosteroids were used during the ICU stay in 189 patients. There was no significant effect of cisatracurium use on the 90-day mortality in the subgroup of patients given corticosteroids (Fig. 6 in the Supplementary Appendix).

Ventilator Settings and Lung FunctionVentilator settings and lung-function variables dur-ing the first week are given in Table 7 in the Sup-plementary Appendix. On day 7, the PaO2:FiO2 ratio was higher, and the PaCO2 value lower, in the cisatracurium group than in the placebo group.

CointerventionsDuring the ICU stay, there were no significant between-group differences in the incidence of cointerventions. A total of 42% of patients in the cisatracurium group and 48% in the placebo group were treated with the use of prone positioning, inhaled nitric oxide, intravenous almitrine mesy-late, or a combination of these (Table 8 in the Sup-plementary Appendix). The criteria for using these interventions were the same in the two groups.

Open-label cisatracurium was given more fre-quently in the placebo group than in the cisatra-cu rium group during the first 48 hours after enrollment. However, the two groups did not dif-fer significantly with respect to the number of pa-tients given at least one open-label cisatracuri um bolus during the entire ICU stay after enrollment (Table 8 in the Supplementary Appendix). The re-quired dose of sedatives or analgesics was similar in the two groups during the first week of the study (Table 9 in the Supplementary Appendix).

SafetyBradycardia developed during the cisatracurium infusion in one patient. No other side effects were reported.

Discussion

Treatment with the neuromuscular blocking agent cisatracurium for 48 hours early in the course of severe ARDS improved the adjusted 90-day sur-vival rate, increased the numbers of ventilator-free days and days outside the ICU, and decreased

the incidence of barotrauma during the first 90 days. It did not significantly improve the overall 90-day mortality.

Strengths of this trial include the methods used to minimize bias (blinded randomization assign-ments, a well-defined study protocol, complete follow-up, and intention-to-treat analyses). The re-cruitment of a large number of patients from 20 multidisciplinary ICUs where international stan-dards of care are followed suggests that our data can be generalized to other ICUs.

Limitations of the trial include the fact that our results were obtained for cisatracurium bes-ylate and may not apply to other neuromuscular blocking agents. Furthermore, we did not assess the use of a neuromuscular blocking agent late in the course of ARDS or use on the basis of plateau-pressure or transpulmonary-pressure measure-ments.20 Another limitation is the absence of data on conditions known to antagonize or potentiate neuromuscular blockade. However, any condition that increases the duration of neuromuscular blockade would have adversely affected the patients receiving the neuromuscular blocking agent, in particular by increasing the duration of mechani-cal ventilation.

The sample-size calculation was based on our two previous studies performed in four ICUs13,15 that used the same inclusion criteria as were used in the current trial and on the European epidemio-logic study ALIVE.4 However, the mortality in the placebo group in this study (40.7%) is lower than

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NMBがARDSの⼈⼯呼吸管理にもたらす影響T h e n e w e ngl a nd j o u r na l o f m e dic i n e

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N Engl J Med 2010;363: 1176-80.

NMBがARDSの⼈⼯呼吸管理にもたらす影響T h e n e w e ngl a nd j o u r na l o f m e dic i n e





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低O2・⾼CO2・反射・不安など↓

呼吸努⼒が上昇→TV上昇

呼吸器との⾮同調

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Barotrauma

肺胞からサイトカインが⾎中に移動

筋収縮により酸素消費↑

肺胞⾎流量↑ ⾎管透過性↑

NMBがARDSの⼈⼯呼吸管理にもたらす影響

N Engl J Med 2010;363: 1176-80.






O2 molecules

Highervenous

PO2

↑ Venous PO2


Less organ

dysfunctionand

failure


effect of NMBA


Patient

Lungvolume


Less volutrauma


No dyssynchrony

No pressure signal

After paralysis

Respiratory cycle



Lower tidal volume

To lungs

To lungs

AlveolusPatient

Lungvolume

Pressuregenerated


Volutrauma

“Atelectrauma”

Dyssynchrony

Dyssynchrony

Before paralysis

Respiratory cycle






O2 molecules

Severelyreduced

venous PO2

↓ Venous PO2

↓ ArterialPO2



permeability

↓↓

↑ ArterialPO2

venous PO



due to:

↓ Arterial PO2

↓ Blood flow

↑ Mediators


Pressure generated

↑ Lung volume

↑ Lung volume

↓ Lung volume

Surfactant

Activeexpiration


blood flow


blood flow

Biotrauma

Lessbiotrauma

Possible↑V/Q

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AuthorFig #

Title

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DEArtist

Issue date

COLOR FIGURE

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Knoper and minions

9/16/10

NMBがARDSの⼈⼯呼吸管理にもたらす影響

N Engl J Med 2010;363: 1176-80.






O2 molecules

Highervenous

PO2

↑ Venous PO2


Less organ

dysfunctionand

failure


effect of NMBA


Patient

Lungvolume


Less volutrauma


No dyssynchrony

No pressure signal

After paralysis

Respiratory cycle



Lower tidal volume

To lungs

To lungs

AlveolusPatient

Lungvolume

Pressuregenerated


Volutrauma

“Atelectrauma”

Dyssynchrony

Dyssynchrony

Before paralysis

Respiratory cycle






O2 molecules

Severelyreduced

venous PO2

↓ Venous PO2

↓ ArterialPO2



permeability

↓↓

↑ ArterialPO2

venous PO



due to:

↓ Arterial PO2

↓ Blood flow

↑ Mediators


Pressure generated

↑ Lung volume

↑ Lung volume

↓ Lung volume

Surfactant

Activeexpiration


blood flow


blood flow

Biotrauma

Lessbiotrauma

Possible↑V/Q

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AuthorFig #

Title

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Issue date

COLOR FIGURE

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•⼈⼯呼吸器と同調• VILI (baro-, volu-, atelec-, biotrauma)が減少•サイトカインが減少•呼吸筋の仕事量減少、肺胞⾎流量の減少•換気⾎流⽐の改善•酸素化の改善• NMBの抗炎症作⽤•臓器障害の進展を抑制

• Reverse trigger• 呼吸時の吸気に関連して、横隔膜が収縮、患者の吸気が誘発される。結果として、過伸展・経肺圧上昇

• Pendelluft• ⾃発呼吸の開始時に、肺内の胸膜圧の変化により腹側(non-dependent)から背側(dependent)に空気が移動。吸気時に腹側が虚脱、背側が過伸展する。

• Ineffective efforts• 患者吸気がトリガされずに、呼気中に吸気が起こる

CHEST 2013;143: 927-938.

Am J Respir Crit Care Med 2013;188:1420-7.

Intensive Care Med. 2017;43 (2):184-191.

Mechanical Ventilation-Induced Reverse-Triggered Breaths CHEST 2013; 143:927–938

• MSICU in Geneva, 2012.1-2012.3• ARDS 8症例のFlow, Paw, Pes or EAdiを測定

Mechanical Ventilation-Induced Reverse-Triggered Breaths CHEST 2013; 143:927–938

journal.publications.chestnet.org CHEST / 143 / 4 / APRIL 2013 931

neural efforts entrained by the ventilator at three different ratios: 1:1, 1:2, and 1:3. We defi ned these neural efforts apparently triggered by the ventilator as “reverse-triggered breaths.” They occurred mainly around the transition phase from mechanical inspira-tion to expiration, remaining unnoticed by the treat-ing physician. These “reverse-triggered breaths” form a potentially common, yet unclassifi ed, form of patient-ventilator interaction.

Pathophysiologic Mechanisms of Respiratory Entrainment

The pathophysiologic mechanisms of “reverse trig-gering,” described in the current study, could be related to the phenomenon of respiratory entrainment, reported only in animals, 4,5,9,11,15,16 healthy humans, 3,6,7 and preterm infants. 17,18 As in the recovery of rhyth-mic limb motor movements after peripheral stimula-tion in spinal cord-injured cats, afferent inputs seem to play a critical role on entrainment generation. 19,20 Failure in the reproduction of the phenomenon in anesthetized animals after bilateral vagotomy has emphasized that slowly adapting stretch receptors, responsible for the Hering-Breuer refl exes, are essential for respiratory entrainment mechanisms. 5,11,15 Despite its fundamental role, the Hering-Breuer refl ex is not the only factor implicated in entrainment phenomena.

Entrainment can be observed after vagal cooling in animals and in healthy subjects who have under-gone a lung transplant. In these scenarios, however, there is a wider distribution around each phase angle and a more limited ventilator rate range. 6,9 Rapidly adapting receptors and vagal C fibers, along with cortical and subcortical infl uences, also seem to be responsible for respiratory rhythm entrainment to the ventilator.

Methodologic Aspects

We initially defi ned entrainment visually, based on the inspection of available recordings, and, provided

that entrainment periods were evident, we proceeded to phase angles calculation. The strength of the entrain-ment was assessed by the SD and the IQR of the phase angles and, additionally, by the variability of the T tot neu. Because respiratory entrainment has not yet been classifi ed formally and various periods or cycle-based defi nitions have been adopted, we rea-soned that the 1:1 entrainment had to be present for a minimum of fi ve consecutive cycles and more complex patterns (ie, 1:2 and 1:3) for a minimum of 10 cycles for entrainment to be characterized as stable. 4,7,9,16,17

Characteristics of Reverse Triggering

Entrainment periods of variable duration and ratios were observed in all consecutive patients studied, causing regular reverse triggering. Our recordings were not specifi cally performed for this purpose, and one may thus hypothesize that the phenomenon is frequent in sedated patients, though scarcely recog-nized under mechanical ventilation. Indeed, respi-ratory entrainment could be reproduced in studies conducted in animals and normal subjects. The true incidence of the phenomenon in the ICU setting needs to be studied.

We believe that the fact that all patients in the cur-rent study had ARDS possibly refl ects (1) the physi-cian’s decision to monitor respiratory mechanics and neural efforts in this specifi c group of patients rather than an association between ARDS and entrainment phenomena, and (2) that this is a group of patients often receiving high doses of sedatives. To what extent the type of critical illness and the magnitude of respi-ratory mechanics’ compromise promote reverse trig-gering remains to be explored.

All patients were deeply sedated as suggested by the low RASS score. Simon et al 7 investigated the effect of the wake state and found that wakefulness and anesthesia, in contrast to non-rapid eye movement sleep, broadened the range of machine frequencies at

Table 2— Sedation Level, Total Recording Time, Entrainment Duration and Ratio, and Arterial Blood Gases in the Eight Patients Tested

Patient No. RASS Recording Time, s

Ratio, % of Entrainment Time

Pa o 2 , mm Hg Pa co 2 , mm Hg pHEntrainment,

s (% of Recording Time) 1:1 1:2 1:3

1 2 5 875 407 (46) 27 66 7 60 46 7.412 2 5 439 58 (13) 0 100 0 55 54 7.303 2 4 467 184 (39) 100 0 0 86 45 7.444 2 5 1658 1,421 (86) 100 0 0 68 47 7.465 2 5 1538 683 (44) 97 3 0 92 30 7.456 2 4 619 619 (100) 100 0 0 74 39 7.257 2 4 365 43 (12) 100 0 0 78 46 7.418 2 5 1295 246 (19) 100 0 0 63 48 7.43

RASS 5 Richmond Agitation and Sedation Scale.

Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 04/04/2013

• Reverse trigger：12-100%で起こる•⼈⼯呼吸器の吸気に関連して、横隔膜が収縮・患者吸気が誘発→ TV増加・過伸展・barotrauma

= P

Pes��

LL

19/04/09「⼈⼯呼吸中の⾃発呼吸を考える」より

Spontaneous Effort Causes Occult Pendelluft during Mechanical Ventilation Am J Respir Crit Care Med 2013; 188: 1420–27

•肺傷害モデルのブタでPendelluft現象を実証

•⾃発呼吸時の陰圧は背側で⼤きい•吸気の始めに、腹側から背側に気体が移動

→腹側：虚脱背側：過伸展

observations in normal lung, in which diaphragmatic contrac-tion triggers local changes in Ppl that are uniformly transmittedacross the entire lung surface (3–7). This principle explains, inpart, why Pes is used as a surrogate of overall Ppl to optimizelung distention, an approach that may improve outcome inpatients with ARDS (18, 20).

In the current study we confirmed that spontaneous effortduring mechanical ventilation in healthy (uninjured) lungsresulted in almost simultaneous inflation throughout the lung.Although inflation of different regions occurred at differentrates, inflation was almost simultaneous in all areas; there wasno significant concomitant deflation (see Figure E1). In addi-tion, airway occlusion tests performed in healthy lung demon-strated that changes in Pes closely matched changes in Paw (andlocal changes in Ppl matched changes in Paw) (see Figure E3).Thus, these observations indicate simultaneous generalizationof local Ppl changes throughout normal lung, supporting theconcept of fluid-like behavior in the (normal) lung (1–7).

However, the pattern of lung inflation was different in thepresence of lung injury. In the injured lung pendelluft occurred.It resulted from the development of a more negative swing in Ppl

in the dependent lung than in the nondependent lung. Acutelung injury involves tissue inflammation and fluid-filled alveoliin a heterogeneous distribution; thus, some areas are well aer-ated and others collapse or fill with fluid and inflammatory cells

(15). Such dense tissue may behave less like a fluid and more asa frame of solid areas resisting shape deformation. In this set-ting, part of the mechanical energy generated by the diaphrag-matic contraction is exerted on local lung deformation ratherthan being transmitted to the rest of the lung; this results inimperfect elastic anisotropic inflation. Because atelectasis inARDS tends to be greater in the dependent and peridiaphrag-matic lung regions (21), such responses might be more markedin these areas. Supporting this idea is the finding that even innormal lung, extreme levels of phrenic nerve stimulation, whichresults in exaggerated diaphragmatic contraction, can causemore negative change in Ppl at the diaphragmatic surface thanin other parts of the lung (3, 5, 6). Thus, even the normal lungmay depart from its fluid-like behavior at extreme levels ofdeformation. We speculate that during injury, this phenomenonis exacerbated and, even at moderate levels of muscle effort, thephysical properties of the lung cannot compensate (i.e., withsufficient rapidity) for dynamic shape changes produced by di-aphragmatic contraction.

An important issue of clinical relevance is that this effect isnot detectable using conventional monitoring. In the currentstudy, demonstration of the effect required dynamic imaging(i.e., EIT or dynamic CT). In addition, although esophagealmonometry (Pes) is becoming a more standard clinical tool forestimation of PL or DPL (18, 20), this technique significantly

Figure 4. Regional distribution of inflation-deflation in lung injury, dynamic computed tomography. When spontaneous breathing effort waspresent, the computed tomography studies showed an intraslice movement of air (from nondependent to dependent zones) in lung slices closeto the diaphragm (deflation from 1 to 2 in nondependent and concomitant inflation from 3 to 4 in dependent regions). This is consistent withpendelluft observed in electrical impedance tomography. Importantly, pendelluft caused tidal recruitment of dependent regions (red) by concom-itant deflating nondependent regions (green).

Yoshida, Torsani, Gomes, et al.: Spontaneous Efforts Cause Occult Pendelluft 1425

Clusters of ineffective efforts during mechanical ventilation: impact on outcome

• Ineffective efforts (IEs)とアウトカムとの関係•前向き観察研究• 2010.1-2011.7, 110 pts., 4,456,537 breaths

Intensive Care Med. 2017;43 :184-191.

189

Although all ‘control’ modes in modern ventilators allow assisted breaths, use of those modes in spontaneously breathing patients varies in everyday practice, and is very limited in our ICU. Thus, it should be emphasized that the observed results are derived from the specific popula-tion studied, and cannot be generalized without further studies.

The value of the obtained results also relies on the method used to identify IEs. The reported sensitivity of the PVI monitor in identifying IEs is 87 % [11], with most cases of missed IEs occurring in patients with very severe flow limitation. In our study, 24 patients (22 %) had a diagnosis of COPD, and only 11 (10 %) were admitted for exacerbation of COPD, suggesting that at least a similar sensitivity could be expected. A similar accuracy in iden-tification of IEs was reported for the software used in the Blanch et al. study [14]. Furthermore, the main results of the study were the same in an analysis of a subgroup of patients, excluding those with COPD (Table S8).

A rather prolonged duration of ventilation and ICU stay was observed in our patients, which could be attrib-uted to the exclusion of patients on CPAP or low assist, and those expected to proceed to a T-piece trial within 24 h of initiation of assisted ventilation. This could be regarded as one of the strengths of the study, as moni-toring of events would be implemented in everyday prac-tice in patients expected to have a relatively long weaning period. However, in our study, the patients were not rig-orously classified into weaning category [19].

Finally, this work was not designed to study the cause of IEs or events, and cannot clarify to what extent the presence of events has a causal relationship with patient outcome. It is reasonable to assume that more severely ill patients having ICU-acquired weakness would have more IEs, and would also require prolonged mechani-cal ventilation [20]. Yet, there are other possible mecha-nisms by which IEs, and particularly events, could be associated with adverse patient outcome. For example, the presence of IEs during expiration would cause pleio-metric contraction to the diaphragm, damaging muscle fibers [21, 22]; discomfort could induce stress [13, 23]; and unrecognized IEs could lead to mistakes in decision-making during weaning [24, 25]. Whether and to what extent IEs are correctable, and whether that would affect patient outcome, were not examined in this study, nor, to our knowledge, in any other past study. However, it is reasonable to assume that appropriate ventilator alarms would significantly facilitate research in this important issue.

In conclusion, this study introduces the concept of events to describe the clusters of ineffective efforts. Not-withstanding that the thresholds used for event definition were rather arbitrary, the presence of events, as well as their power and duration, are associated with prolonged duration of mechanical ventilation and higher hospi-tal mortality. As the computation of an event can be performed in real time, through the use of appropriate

a

b

c

Fig. 2 Duration in days of ICU stay, and mechanical ventilation, in total (MV-total), and after the first recording (MV-post), for patients with events (teal), and without (orange). a 1st day group (n = 79), b all patients (n = 110), c patients with an IEs index less than 10 % (n = 97), *p < 0.05, **p < 0.01, box and whiskers at 10–90 %, line at median

IEs：患者吸気がトリガされず呼気中に患者吸気が起こる→ breath stacking、過伸展

• 42/110 pts.(38.2%)で出現• ICU滞在⽇数・MV期間・院内死亡率上昇

ATS/ESICM/SCCMのガイドライン

üNMBに関しては、情報が限定されていてるため評価せず

ü次回以降のガイドラインでは、NMBに対しての項⽬が記載されるだろう

AMERICAN THORACIC SOCIETYDOCUMENTS

An Official American Thoracic Society/European Society of IntensiveCare Medicine/Society of Critical Care Medicine Clinical PracticeGuideline: Mechanical Ventilation in Adult Patients with AcuteRespiratory Distress SyndromeEddy Fan, Lorenzo Del Sorbo, Ewan C. Goligher, Carol L. Hodgson, Laveena Munshi, Allan J. Walkey,Neill K. J. Adhikari, Marcelo B. P. Amato, Richard Branson, Roy G. Brower, Niall D. Ferguson, Ognjen Gajic,Luciano Gattinoni, Dean Hess, Jordi Mancebo, Maureen O. Meade, Daniel F. McAuley, Antonio Pesenti,V. Marco Ranieri, Gordon D. Rubenfeld, Eileen Rubin, Maureen Seckel, Arthur S. Slutsky, Daniel Talmor,B. Taylor Thompson, Hannah Wunsch, Elizabeth Uleryk, Jan Brozek, and Laurent J. Brochard; on behalf of theAmerican Thoracic Society, European Society of Intensive Care Medicine, and Society of Critical Care Medicine

THIS OFFICIAL CLINICAL PRACTICE GUIDELINE OF THE AMERICAN THORACIC SOCIETY (ATS), EUROPEAN SOCIETY OF INTENSIVE CARE MEDICINE (ESICM), AND

SOCIETY OF CRITICAL CARE MEDICINE (SCCM) WAS APPROVED BY THE ATS, ESICM, AND SCCM, MARCH 2017

Background: This document provides evidence-basedclinical practice guidelines on the use of mechanical ventilationin adult patients with acute respiratory distress syndrome (ARDS).

Methods: A multidisciplinary panel conducted systematic reviewsand metaanalyses of the relevant research and applied Grading ofRecommendations, Assessment, Development, and Evaluationmethodology for clinical recommendations.

Results: For all patients with ARDS, the recommendation is strong formechanical ventilation using lower tidal volumes (4–8 ml/kg predictedbodyweight) and lower inspiratory pressures (plateau pressure, 30 cmH2O) (moderate confidence in effect estimates). For patients with severeARDS, the recommendation is strong for prone positioning for more

than 12 h/d (moderate confidence in effect estimates). For patients withmoderateor severeARDS, the recommendation is strongagainst routineuse of high-frequency oscillatory ventilation (high confidence in effectestimates) and conditional for higher positive end-expiratory pressure(moderate confidence in effect estimates) and recruitment maneuvers(low confidence in effect estimates). Additional evidence is necessary tomake a definitive recommendation for or against the use ofextracorporeal membrane oxygenation in patients with severe ARDS.

Conclusions: The panel formulated and provided the rationale forrecommendations on selected ventilatory interventions for adultpatients with ARDS. Clinicians managing patients with ARDS shouldpersonalize decisions for their patients, particularly regarding theconditional recommendations in this guideline.

ContentsOverviewIntroductionMethods

Committee CompositionConfidentiality Agreement andConflict-of-InterestManagement

MeetingsFormulating Clinical QuestionsLiterature SearchEvidence Review andDevelopment of ClinicalRecommendations

Manuscript PreparationRecommendations for SpecificTreatment Questions

Question 1: Should Patientswith ARDS ReceiveMechanical Ventilation UsingLTVs and InspiratoryPressures?

Question 2: Should Patientswith ARDS Receive PronePositioning?

Question 3: Should Patients withARDS Receive High-FrequencyOscillatory Ventilation?

Question 4: Should Patients withARDS Receive Higher, asCompared with Lower, PEEP?

Question 5: Should Patients withARDS Receive RMs?

Question 6: Should Patients withARDS Receive ExtracorporealMembrane Oxygenation?

Conclusions

Correspondence and requests for reprints should be addressed to Eddy Fan, M.D., Ph.D., Toronto General Hospital, 585 University Avenue, PMB 11-123,Toronto, Ontario, M5G 2N2 Canada. E-mail: [email protected]

Am J Respir Crit Care Med Vol 195, Iss 9, pp 1253–1263, May 1, 2017Copyright © 2017 by the American Thoracic SocietyDOI: 10.1164/rccm.201703-0548STInternet address: www.atsjournals.org

American Thoracic Society Documents 1253

Am J Respir Crit Care Med 2017; 195: 1253-63.

⽇本集中治療医学会・⽇本呼吸療法医学会・⽇本呼吸器学会３学会・２委員会合同

ARDS診療ガイドライン2016

Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries JAMA. 2016;315(8):788-800.

Copyright 2016 American Medical Association. All rights reserved.

Table 4. Use of Adjunctive and Other Optimization Measures in Invasively Ventilated PatientsWith Acute Respiratory Distress Syndromea

Patients of No. (%) [95% CI]

P ValuebAll(n = 2377)

Milda

(n = 498)Moderatea

(n = 1150)Severea

(n = 729)Neuromuscularblockade

516 (21.7)[20.1-23.4]

34 (6.8)[4.8-9.4]

208 (18.1)[15.9-20.4 ]

274 (37.8)[34.1-41.2]

<.001

Recruitmentmaneuvers

496 (20.9)[19.2-22.6]

58 (11.7)[9.0-14.8]

200 (17.4)[15.2-19.7]

238 (32.7)[29.3-36.2]

<.001

Prone positioning 187 (7.9)[6.8-9.0]

5 (1.0)[0.3-2.3]

63 (5.5)[4.2-7.0]

119 (16.3)[13.7-19.2]

<.001

ECMO 76 (3.2)[2.5-4.0]

1 (0.2)[0.05-1.2]

27 (2.4)[1.6-3.4]

48 (6.6)[4.9-8.6]

<.001

Inhaled vasodilators 182 (7.7)[6.6-8.8]

17 (3.4)[02.0-5.4]

70 (6.1)[4.8-7.6]

95 (13.0)[10.7-15.7]

<.001

HFOV 28 (1.2)[0.8-1.7]

3 (0.6)[0.1-1.7]

14 (1.2)[0.7-2.0]

11 (1.5)[0.8-2.7]

.347

None of the above 1431 (60.2)[58.2-62.2]

397 (79.7)[75.9-83.2]

750 (65.2)[62.4-68.0]

284 (39.0)[35.4-42.6]

<.001

Esophageal pressurecatheter

19 (0.8)[0.04-1.4]

2 (0.4)[0.04-1.4]

8 (0.7)[0.3-1.3]

9 (1.2)[0.6-2.3]

.233

Tracheostomy 309 (13.0)[11.6-14.4]

48 (9.6)[7.1-12.6]

155 (13.5)[11.6-15.6]

106 (14.5)[12.1-17.3]

.034

High-dosecorticosteroidsc

425 (17.9)[16.4-19.5]

61 (12.3)[9.5-15.5]

194 (16.9)[14.7-19.2]

170 (23.3)[20.3-26.6]

<.001

Pulmonary arterycatheter

107 (4.5)[3.7-5.4]

9 (1.8)[0.8-3.4]

53 (4.6)[3.4-6.0]

45 (6.2)[4.5-8.2]

.001

Abbreviations: ARDS, acuterespiratory distress syndrome;ECMO, extracorporeal membraneoxygenation; HFOV, high-frequencyoscillatory ventilation; PEEP, positiveend-expiratory pressure.a For this analysis, ARDS severity was

defined based on the patients’worst severity category over thecourse of their ICU stay in patientswho developed ARDS on day 1 or 2.

b P value represents comparisonsacross the ARDS severity categoriesfor each variable.

c High-dose corticosteroids wasdefined as doses that were equalto or greater than the equivalentof 1 mg/kg of methylprednisolone.

Table 5. Outcome of Invasively Ventilated Patients by Acute Respiratory Distress Syndrome Severity at Diagnosis

ParameterAll(n = 2377)

Mild(n = 714)

Moderate(n = 1106)

Severe(n = 557) P Valuea

Progression of ARDS severity,No (%) [95% CI]b

Progression to moderatec 184 (25.8)[22.6-29.1]

N/A N/A

Progression to severec 32 (4.5)[3.1-6.3]

140 (12.7)[10.8-14.8]

N/A

Death in the 1st wk without category change 63 (8.8)[6.8-11.1]

126 (11.4)[9.6-13.4]

117 (21.0)[17.7-24.6]

Invasive ventilation-free days to day 28,median (IQR), dd

10 (0-22) 16 (0-24) 11 (0-21) 0 (0-18) <.001

Duration of invasive ventilation,median (IQR), d

All patients 8 (4-15) 7 (3-14) 8 (4-16) 9 (4-16) .04

Surviving patients 8 (4-15) 6 (3-13) 8 (4-15) 11 (6-18) <.001

ICU length of stay, median (IQR), d

All patients 10 (5-20) 10 (5-19) 11 (6-20) 11 (5-19) .39

Surviving patients 11 (7-21) 10 (6-19) 12 (7-21) 14 (7-23) .03

ICU mortality, No. (%) [95% CI] 838 (35.3)[33.3-37.2]

212 (29.7)[26.4-33.2]

387 (35.0)[32.2-37.9]

239 (42.9)[38.8-47.1]

<.001

Day 28 mortality, No. (%) [95% CI] 828 (34.8)[32.9-36.8]

211 (29.6)[26.2-33.0]

389 (35.2)[32.4-38.1]

228 (40.9)[36.8-45.1]

<.001

Hospital length of stay, median (IQR), d

All patients 17 (8-33) 18 (10-33) 17 (8-33) 16 (6-31) .22

Surviving patients 23 (14-40) 23 (14-40) 22 (13-40) 26 (14-43) .41

Hospital mortality, No. (%) [(95% CI] 952 (40.0)[38.1-42.1]

249 (34.9)[31.4-38.5]

446 (40.3)[37.4-43.3]

257 (46.1)[41.9-50.4]

<.001

Abbreviations: ARDS, acute respiratory distress syndrome, ICU, intensive careunit; IQR, interquartile range.a P value represents comparisons across the ARDS severity categories

for each variable.b Initial ARDS severity determined from worst partial pressure of oxygen

to fraction of inspired oxygen ratio within first 24 hours followingARDS diagnosis.

c Most severe is calculated for time period up to day 7 postdiagnosis of ARDS.Analysis was limited to the first 7 days due to the less frequent samplingafter that day.

d In patients in whom death occurs while receiving invasive mechanicalventilation, invasive ventilation-free days are counted as 0.

Research Original Investigation Trends in Acute Respiratory Distress Syndrome in 50 Countries

794 JAMA February 23, 2016 Volume 315, Number 8 (Reprinted) jama.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Saitama Medical University User on 09/16/2016

•全体で21.7%Mild: 6.8%, Moderate: 18.1%, Severe: 37.8%

•重症例でより多く使⽤されている

NMBの⻑期使⽤ → ICU-AWとの関連

Copyright © 2016 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Review Article

#RITICAL�#ARE�-EDICINE� www.ccmjournal.org 2075

Second, our sensitivity analyses found that studies limited to patients with severe sepsis or septic shock demonstrated the strongest association between NMBAs and neuromuscular dysfunction acquired in critical illness; inadequate reporting

of patients with sepsis (as opposed to severe sepsis or septic shock) precluded this group from being included in this analy-sis. Both of the studies in the severe sepsis or septic shock sensi-tivity analysis evaluated for CIP. The first case series to describe

CIP, published by Bolton et al (34) in 1984, implicated sepsis in its pathogenesis. Subsequent analyses that adjusted for con-founders (13) also supported sepsis as an independent risk factor. Our analysis provides additional support that an association between NMBAs given to patients with sepsis and neuromuscular dysfunc-tion acquired in critical ill-ness exists, and consistent with prior work (9, 29), the association may be propor-tional to the severity of sepsis. Specifically, as demonstrated in Supplemental Figure 1h (Supplemental Digital Content 6, http://links.lww.com/CCM/B854; legend, Supplemental Digital Content 7, http://links.lww.com/CCM/B855),

Figure 2. Primary analysis: Forest plot of all included studies.

Figure 3. Primary analysis: Funnel plot of all included studies. OR = odds ratio.

Neuromuscular Blocking Agents and Neuromuscular Dysfunction Acquired in Critical Illness: A Systematic Review and Meta-Analysis Crit Care Med 2016; 44:2070–78

Neuromuscular Blockade and Skeletal Muscle Weakness in Critically Ill Patients

Am J Respir Crit Care Med 2012; 185: 911–7

SEDATION AS A POTENTIAL RISK FACTOR FOR ICU-AW

NMBA use, and subsequent immobilization, must always be ac-companied by appropriate levels of sedation, which also sustainimmobilization. Indeed, inadequate use of sedation in conjunc-tion with NMBAs may exacerbate psychosocial morbidity inICU survivors, although this is beyond the remit of this review.Prolonged immobilization results in electrophysiological dys-function, decreased muscle protein synthesis, loss of musclemass, and microvascular dysfunction (73–76). Although bedrest, antigravity, and hind limb suspension models simulate im-mobility, sedation should also be considered as an independentrisk factor above the effects on immobilization. Propofol andbenzodiazepines positively modulate the inhibitory function ofthe neurotransmitter g-amino-butyric acid (GABA) (77, 78).GABA facilitates the opening of the voltage-gated chloridechannels in skeletal muscle, which decreases muscle excitability(78, 79). Barbiturates and ketamine attenuate the response ofexcitatory neurotransmitters such as glutamate, decreasing mus-cle tone by acting on motor-associated neurons in the spinalcord via N-methyl-D-aspartate (NMDA) receptors (78, 80, 81).Thus, continued sedation could be expected to have a greatereffect on muscle atrophy and muscle weakness than the conven-tional awake human and animal immobility models. This couldexplain the results of previous studies that have shown thatICU-AW was greater in those patients exposed to a higher sed-ative load (71). It is therefore reasonable to postulate the bene-ficial physical effects observed in studies using sedation protocols

with sedation holds and reduced sedation load (82–85) are poten-tially the direct result of decreased frequency and severity of ICU-AW. There are no published data investigating the association ofsedation level with ICU-AW or patient arousal and activity andICU-AW.With current prevailing clinical practice favoring amoreminimalistic approach to sedation and a proactive approach tomobilization (82–84, 86), clinicians may focus further on reducingthe use of sedatives.

APPLICATION OF HISTORIC NMBA DATA IN THE 21STCENTURY CRITICAL CARE SETTING

To interpret previous studies objectively, we need to consider thepatient groups investigated and their clinical management. Itmust be acknowledged that the majority of data from previousuncontrolled studies indicating a causal relationship betweenNMBAs and ICU-AW were observations made during the lastcentury (Table 1). Clinical practice has changed significantlyover the last 20 years. The majority of patients included in thesestudies had primary ventilatory failure, and strategies of me-chanical ventilation were markedly different from those cur-rently practiced. In the 1980s and early 1990s, the mostcommon ventilators used lacked the ability to support sponta-neous ventilation through pressure-support (PS) modes,whereas others lacked a synchronized intermittent mandatorymode of ventilation. The commonest weaning mode used in theUnited States in the late 1980s was the use of mandatory breathsfrom intermittent mandatory ventilation, supplemented by

TABLE 1. OBSERVATIONAL STUDIES INVESTIGATING THE RELATIONSHIP BETWEEN NEUROMUSCULAR BLOCKING AGENTS USE ANDINTENSIVE CARE–ACQUIRED WEAKNESS

Author

Year of

Study

Mean

Age (yr) Diagnosis

Mean APACHE

Score (SD) Design

Frequency

of ICU-AW Steroid Use

Neuromuscular

1Blocking

Agent Used

Mean Length

of Use of

Neuromuscular

Blocking Agent

(d )

Days Ventilated

Prediagnosis

of ICU-AW

Diagnostic

Method

for ICU-AW

Association with

Neuromuscular

Blocking Agent

Leijten et al.

(117)

1995 ,75 Heterogeneous Not reported Prospective

observational

29/50 Not

recorded

Vecuronium Not reported Not standardized EP Testing N (U)

Latronico

et al. (70)

1996 50.2 Heterogeneous Not reported Prospective

observational

24/24 4/24 Pancuronium or

atracurium

For procedures

only

Not standardized Clinical

examination

N (U)

Kesler

et al. (98)

2009 39 Asthma Not reported Retrospective

observational

10/74 All Vecuronium or

atracurium

2 patients Not standardized Clinical

examination

N (U)

Leatherman

et al. (97)

1996 38 Asthma Not reported Retrospective

observational


atracurium

1 Not standardized Clinical

examination

N (U)

Behbehani

et al. (67)

1999 47 Asthma 14.3 (6.2) Retrospective

observational


pancuronium

3.1 Not standardized Clinical

examination

Y (M)

Segredo

et al. (66)

1992 45 Respiratory

failure

Not reported Prospective

observational

7/16 None Vecuronium 7 Not standardized EP testing* Y (U)

Witt et al.

(118)

1991 43 Heterogeneous Not reported Prospective

observational

30/43 Not

recorded

Not recorded Not reported Not standardized EP testing N (M)

Douglass

et al. (31)

1992 N/A Asthma Not reported Prospective

observational

9/25 All Vecuronium Not available Not standardized Clinical

examination

Y (U)

Adnet

et al. (68)

1995–1999 40 Asthma Not reported Retrospective

observational

10/55 All Pancuronium or

vecuronium

4.2 Not standardized Clinical

examination

Y (M)

Nanas et al.

(119)

2005–2006 55 Heterogeneous 15 (7) Prospective

observational

50/474 38/474 Not recorded 61 patients Not standardized Clinical

examination

N (M)

De Jonghe

et al. (5)

1999–2000 62 Heterogeneous SAPS II 48.7 Prospective

observational

23/95 26/95 Vecuronium 3.3 .7 Clinical

examination

N (U, M)

Garnacho-

Montero

et al. (69)

1996–1999 62 Heterogeneous 17.5 (6.9) Prospective

observational

46/73 11/73 Vecuronium or

atracurium

10/73 .10 EP testing Y (M)

Campellone

et al.

(120)

1995–1995 53 Liver

transplantation

24.4 Prospective

observational

8/77 All Pancuronium or

vecuronium

Not reported .7 Clinical

examination

N (U,M)

de Letter

et al.

(121)

1994–1996 70 Heterogeneous Not reported Prospective

observational

32/98 34/98 Vecuronium Not reported .15 Clinical

examination

N (M)

Garnacho-

Montero

et al. (71)

1999–2002 61 Severe/sepsis 22.2 Prospective

observational

34/64 Not

reported

Vecuronium or

atracurium

13/64 Not standardized EP testing N (M)

Bednarik

et al.

(122)

2000–2002 59 Multiorgan

failure

SOFA 7 Prospective

observational

17/61 None Pipecuronium Not reported Not standardized Clinical

examination

N (M)

Definition of abbreviations: EP testing ¼ electrophysiological testing; ICU-AW ¼ intensive care unit–acquired weakness; M ¼ multivariate; N ¼ no; U ¼ univariate; Y ¼ yes.*Limited to ulnar nerve stimulation.

Occasional Essay 913

ACURASYSの問題点• 2006-2008年の研究

→ ARDSの管理がここ10年で変わってきている• NMB + Deep sedation vs. Deep sedation

→ Light sedationの⽅がMV期間や死亡率が改善

•両群はLow PEEPで設定→重症ARDSはPEEPを⾼めで管理

Am J Respir Crit Care Med 2012;186:724-31.Crit Care Med 2018; 46:850-9.

ACURASYSの問題点• 2⽇間の使⽤で、予後が18⽇以降で差が出る• P/F<120で差が出る（<150では同等）• NMBはVILIやbiotraumaを低下させるとなっているが、確証はされていない• TV, Pplatには変化がない

NMB + Deep sedation vs. Light sedation with High PEEPでの検討が必要



The members of the writing committee (Marc Moss, M.D., David T. Huang, M.D., M.P.H., Roy G. Brower, M.D., Niall D. Ferguson, M.D., Adit A. Ginde, M.D., M.P.H., M.N. Gong, M.D., Colin K. Gris-som, M.D., Stephanie Gundel, M.S., Douglas Hayden, Ph.D., R. Duncan Hite, M.D., Peter C. Hou, M.D., Catherine L. Hough, M.D., Theodore J. Iwashyna, M.D., Ph.D., Akram Khan, M.D., Kathleen D. Liu, M.D., Ph.D., Daniel Talmor, M.D., M.P.H., B. Taylor Thompson, M.D., Christine A. Ulysse, Ph.D., Donald M. Yealy, M.D., and Derek C. Angus, M.D., M.P.H.) as-sume responsibility for the overall con-tent and integrity of this article. The affili-ations of the members of the writing committee are listed in the Appendix. Address reprint requests to Dr. Angus at the University of Pittsburgh, 3550 Terrace St., Pittsburgh, PA 15261, or at angusdc@ upmc . edu.

*A full list of the investigators in the Re-evaluation of Systemic Early Neuro-muscular Blockade (ROSE) trial and the Prevention and Early Treatment of Acute Lung Injury (PETAL) network is provided in the Supplementary Appen-dix, available at NEJM.org.

This article was published on May 19, 2019, at NEJM.org.

DOI: 10.1056/NEJMoa1901686Copyright © 2019 Massachusetts Medical Society.

BACKGROUNDThe benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear.

METHODSWe randomly assigned patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ≥8 cm of water) to a 48-hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical-ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in-hospital death from any cause at 90 days.

RESULTSThe trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, −0.3 percentage points; 95% confidence interval, −6.4 to 5.9; P = 0.93). While in the hospital, patients in the intervention group were less physi-cally active and had more adverse cardiovascular events than patients in the con-trol group. There were no consistent between-group differences in end points as-sessed at 3, 6, and 12 months.

CONCLUSIONSAmong patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets. (Funded by the National Heart, Lung, and Blood Institute; ROSE ClinicalTrials.gov number, NCT02509078.)

A BS TR AC T

Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome

The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network*

Original Article



ROSE trial - PETAL : Prevention and Early Treatment of Acute Lung Injury - ROSE : Reevaluation of Systemic Early Neuromuscular Blockade

METHODS

P：中等度〜重症のARDS患者 (P/F < 150)

I：早期にCisatracuriumを48時間持続投与

C：通常の管理

O：90⽇死亡率

• 2016.1 – 2018.4• 48 hospitals in U.S.• 18歳以上•発症から48時間以内• P/F < 150 (PEEP 8cmH20以上)•胸⽔・無気肺・結節では説明できない両側浸潤影•⼼不全や輸液負荷では説明できない呼吸不全

Patients

Exclusion criteria• 同意が取れない• 登録前にNMBが投与されていた• ECMOを導⼊されていた• 慢性呼吸不全：PaCO2 > 60mmHg• ⾃宅で呼吸器を使⽤（SAS除く）• 肥満：1kg/cm以上• 肝硬変：Child-Pugh 12-15• 1年以内の⾻髄移植• MVが48時間以内と予想される• 延命治療を希望しない• 24時間以内に死亡が予測される

Patients

• ⾎管炎由来のびまん性肺胞出⾎• TBSA >70%の熱傷• TV 6ml/kgが適応できない• Cisatracuriumに対するアレルギー• 神経筋疾患の既往• ICHの治療をしている• ARDSの介⼊研究に登録済み• ランダム化前にP/F >200に改善• 5⽇以上挿管されている• 肺移植の待機患者

NMB群• Deep sedation (RASS -4-5, SAS 5-6, RSS 1-2)：割付後4時間以内に達成

• Cisatracurium：15mg bolus + 37.5mg/hr 48hrs

•末梢神経刺激による投与量の調整はなし• NMBの早期終了：FiO2 <0.4, PEEP <8 cmH20を12時間維持

コントロール群• Light sedation

- RASS：0, -1- SAS：3, 4- RSS：2, 3

•ルーティンのNMBの使⽤はしない

共通項⽬呼吸器管理• Low tidal volume 6ml/kg PBW：割付後2時間以内• High PEEP strategy：割付後5⽇間• 酸素化悪化・低⾎圧・Pplat >30cmH2O・pH<7.15が予想されるときはPEEPを下げることは可能• 気胸出現・barotraumaのリスクが⾼い患者には、

PEEPは下げて対応

•腹臥位療法は臨床医の判断に委ねる

ROSE NMB Version III PETAL Network August 31, 2015 50 | P a g e

8. Oxygenation target: 55 mmHg < PaO2 < 80 mm Hg or 88% < SpO2 < 95%. When both PaO2 and SpO2 are available simultaneously, the PaO2 criterion will take precedence.

9. Minimum PEEP = 5 cm H20 10. Adjust FiO2 or PEEP upward within 5 minutes of consistent measurements below the

oxygenation target range 11. Adjust FiO2 or PEEP downward within 30 minutes of consistent measurements above

the oxygenation target range. 12. The below high PEEP strategy FiO2/PEEP table, modified from the ALVEOLI trial ,

should be used in all patients. See Section 5.3.3 for when deviation is permitted..

FiO2 .30 .40 .50 .60 .70 .80 .90 1.0

PEEP 5 5-16 16-20 20 20 20-22 22 22.24

(Levels of PEEP in these FiO2 / PEEP scales represent levels set on the ventilator, not levels of total-PEEP, auto-PEEP, or intrinsic-PEEP.)

13. No specific rules for respiratory rate, but incremental increase in the RR to maximum set rate of 35 if pH < 7.30.

14. No specific rules about I:E. Recommend that duration of Inspiration be ≤ duration of Expiration.

15. Bicarbonate is allowed (neither encouraged nor discouraged) if pH < 7.30.

Changes in more than one ventilator setting driven by measurements of PaO2, pH, and Pplat may be performed simultaneously, if necessary.

D.2 WEANING Commencement of weaning

Patients will be assessed for the following weaning readiness criteria each day between 0600 and 1000. If a patient procedure, test, or other extenuating circumstance prevents assessment for these criteria between 0600 and 1000, then the assessment and initiation of subsequent weaning procedures may be delayed for up to six hours. Patients can be assessed for weaning readiness criteria twice a day.

1. At least 12 hours since enrollment in the trial. 2. FiO2 d 0.40 and PEEP d 8 cm 3. Values of both PEEP and FiO2 d values from previous day (comparing Reference

Measurement values, section 6.3). 4. Systolic arterial pressure t 90 mm Hg without vasopressor support (d 5 mcg / kg / min

dopamine or dobutamine will not be considered a vasopressor).

Spontaneous breathing trial (SBT) procedure and assessment for unassisted breathing

If criteria 1-4 above are met, first the neuromuscular blocking agent will need to be discontinued if the medication is still being infused. When the neuromuscular blocking agent has worn off and

共通項⽬NMB投与•以下の時、Cisatracurium 20mgボーラスが可能• 鎮静薬・TV/PEEPを調整してもPplat >30cmH2Oが10分以上続く場合• Pplatが2cmH2O以上低下すれば、再度NMB投与は可能、下がらないなら24時間は投与しない

• 48時間経過後、NMBの継続をするかは臨床医に委ねられる•⽐較しやすいようにNMBはCisatracurium換算

Trial design

ü筋弛緩薬の種類・投与量・投与期間はACURASYSと同様

üコントロール群はLight sedation

ü両群ともLow TV ventilation + high PEEP protocol

ü輸液⽅法もConservative fluid strategyを使⽤

End points

• Primary end point• 90⽇死亡率

• Secondary end point• SOFA score• 28⽇死亡率• ICU⽇数、MV⽇数• 3, 6, 12ヶ⽉後に⾝体機能や精神状態などを評価• Safety end point

Statistical analysis

•死亡率：NMB群 27%, コントロール群 35%•検出⼒ 90%、有意⽔準 0.05

→ 1408⼈• Primary end point：Wald検定•サブグループ解析：⼀般線形モデル

ARDS重症度 (P/F 120)、ARDS期間 (登録〜割付の中央値)、登録前NMB使⽤率が多い病院、性別、⼈種、⺠族

Statistical analysis

• Adverse events：ポアソン回帰分析• Nonserious - 1, serious - 2

• 90⽇/1年死亡率：Z検定

•全てIntension-to-treatで解析• SAS version 9.4

RESULTS

Patient flow chart


Early Neuromuscular Block ade in ARDS

Figure 1. Patient Screening, Enrollment, and Follow-up.

Patients may have had more than one reason for exclusion. Two patients were randomly assigned twice to the con-trol group. No patients were lost to follow-up. NMB denotes neuromuscular blockade, and PaO2:FIO2 the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen.

1008 Underwent randomization

4848 Patients were assessed for eligibility

3840 Were excluded658 Had PaO2:FIO2 >200 mm Hg at time

of randomization655 Were receiving continuous NMB

at enrollment394 Declined to participate or had surrogate

who declined384 Were not expected to survive 24 hr307 Were withdrawn by physician270 Did not have surrogate available245 Had been receiving mechanical ventilation

for >120 hr237 Had severe chronic liver disease209 Had inclusion criteria for >48 hr159 Decided to withhold life-sustaining

treatment124 Had body weight >1 kg/cm of height113 Were receiving extracorporeal membrane

oxygenation109 Were expected to receive mechanical

ventilation for <48 hr561 Had other reason

502 Were assigned to the intervention group(cisatracurium) 506 Were assigned to the control group

86 Received any NMB in the first 48-hrintervention period

40 Received any NMB in the second48-hr trial period

501 Were included in the primary analysis 505 Were included in the primary analysis

1 Was immediately withdrawnfrom the trial after randomization

owing to ineligibility and didnot receive cisatracurium


owing to ineligibility and didnot receive NMB

488 Received cisatracurium in the first48-hr intervention period

13 Did not receive cisatracurium in first 48-hrintervention period

3 Were withdrawn before administrationof NMB

1 Was deemed too unstable by physician2 Died before administration of NMB1 Did not reach target sedation6 Had other reasons

419 Did not receive any NMB in the second 48-hr trial period



2回⽬の中間解析で無益と判断され中断

658⼈：P/F>200に改善655⼈：NMB投与済み394⼈：参加を辞退307⼈：医師による取り下げ

1008

Patient flow chart



Figure 1. Patient Screening, Enrollment, and Follow-up.

Patients may have had more than one reason for exclusion. Two patients were randomly assigned twice to the con-trol group. No patients were lost to follow-up. NMB denotes neuromuscular blockade, and PaO2:FIO2 the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen.

1008 Underwent randomization

4848 Patients were assessed for eligibility

3840 Were excluded658 Had PaO2:FIO2 >200 mm Hg at time

of randomization655 Were receiving continuous NMB

at enrollment394 Declined to participate or had surrogate

who declined384 Were not expected to survive 24 hr307 Were withdrawn by physician270 Did not have surrogate available245 Had been receiving mechanical ventilation

for >120 hr237 Had severe chronic liver disease209 Had inclusion criteria for >48 hr159 Decided to withhold life-sustaining

treatment124 Had body weight >1 kg/cm of height113 Were receiving extracorporeal membrane

oxygenation109 Were expected to receive mechanical

ventilation for <48 hr561 Had other reason

502 Were assigned to the intervention group(cisatracurium) 506 Were assigned to the control group

86 Received any NMB in the first 48-hrintervention period

40 Received any NMB in the second48-hr trial period

501 Were included in the primary analysis 505 Were included in the primary analysis


owing to ineligibility and didnot receive cisatracurium


owing to ineligibility and didnot receive NMB

488 Received cisatracurium in the first48-hr intervention period

13 Did not receive cisatracurium in first 48-hrintervention period

3 Were withdrawn before administrationof NMB

1 Was deemed too unstable by physician2 Died before administration of NMB1 Did not reach target sedation6 Had other reasons

419 Did not receive any NMB in the second 48-hr trial period



501 505

Intervention Control

Cisatracurium・0-48hr：488⼈・48-96hr：69⼈

Cisatracurium・0-48hr：86⼈

・48-96hr：40⼈

502 506



CharacteristicIntervention Group

(N = 501)Control Group

(N = 505)

Age — yr 56.6±14.7 55.1±15.9

Female sex — no. (%)† 210 (41.9) 236 (46.7)

White race — no. (%)† 361 (72.1) 344 (68.1)

Shock at baseline — no. (%) 276 (55.1) 309 (61.2)

Median time from enrollment to randomization (IQR) — hr

8.2 (4.0–16.4) 6.8 (3.3–14.5)

Neuromuscular blockade use between meeting inclusion criteria and randomization — no./total no. (%)

55/484 (11.4) 50/484 (10.3)

Primary cause of lung injury — no. (%)

Pneumonia 292 (58.3) 301 (59.6)

Aspiration 91 (18.2) 75 (14.9)

Nonpulmonary sepsis 68 (13.6) 71 (14.1)

Other cause 50 (10.0) 58 (11.5)

Assessments and measurements

APACHE III score‡ 103.9±30.1 104.9±30.1

Total SOFA score§ 8.7±3.6 8.8±3.6

Tidal volume — ml/kg of predicted body weight¶ 6.3±0.9 6.3±0.9

FIO2∥ 0.8±0.2 0.8±0.2

Inspiratory plateau pressure — cm of water** 25.5±6.0 25.7±6.1

PEEP — cm of water†† 12.6±3.6 12.5±3.6

PaO2:FIO2 — mm Hg‡‡ 98.7±27.9 99.5±27.9

Imputed PaO2:FIO2 — mm Hg§§ 94.8±26.7 93.2±28.9

* Plus–minus values are means ±SD. There were no significant differences between the groups except for time from inclusion in the trial to randomization (P = 0.047) and shock at baseline (P = 0.05). Percentages may not total 100 because of rounding. IQR denotes interquartile range.

† Sex and race were determined by the coordinators on the basis of hospital records or information from the next of kin.

‡ Acute Physiology, Age, and Chronic Health Evaluation (APACHE III) scores range from 0 to 299, with higher scores indicating more severe illness.41 The APACHE III score was assessed in 455 patients in the intervention group and 459 in the control group.

§ Sequential Organ Failure Assessment (SOFA) scores were measured in 5 organ systems (respiratory, cardiovascular, hematologic, gastrointestinal, and renal; the neurologic system was not assessed), with each organ scored from 0 to 4, resulting in an aggregated score that ranges from 0 to 20, with higher scores indicating greater dysfunction.28 The SOFA score was not assessed in 1 patient in the control group.

¶ The tidal volume was assessed in 445 patients in the intervention group and 443 in the control group.∥ The fraction of inspired oxygen (FIO2) was assessed in 469 patients in the intervention group and 474 in the control

group.** The inspiratory plateau pressure was assessed in 274 patients in the intervention group and 266 in the control group.†† The positive end-expiratory pressure (PEEP) was assessed in 492 patients in the intervention group and 495 in the

control group.‡‡ The ratio of the partial pressure of arterial oxygen (PaO2) to FIO2 was assessed in 452 patients in the intervention group

and 460 in the control group. The FIO2 value reflects the value that was recorded closest to the time of randomization within the 24 hours before randomization.

§§ If an arterial blood gas analysis was not available at randomization, the PaO2:FIO2 could be inferred from the oxygen saturation as measured by pulse oximetry. The imputed PaO2:FIO2 was calculated in 49 patients in the intervention group and 45 patients in the control group.

Table 1. Baseline Characteristics of the Patients.*



P=0.047

P=0.05

• 約70%が⽩⼈• コントロール群でショックが多い：55.1% vs. 62.2%

• NMB群で登録から割付までの時間が⻑い：8.2hr vs. 6.8hr

全体の中央値は7.6hr (3.7-15.6)• 原因の60%は肺炎• P/F 100、FiO2 0.8、PEEP 12

筋弛緩

NMB群• 488 (97.4%)がcisatracuriumを投与•割付から1.9±1.4時間後に投与•投与期間：47.8hr (43.8-48.0)•状態改善による早期中⽌：74 (14.8%)

コントロール群• 86 (17.0%)がcisatracuriumを投与 (最初の48時間)•投与量：38mg (14-200)

筋弛緩



a neuromuscular blocking agent during the first 48 hours at a median cisatracurium (or equivalent) dose of 38 mg (interquartile range, 14 to 200). Additional details on the dosing of neuromuscu-lar blocking agents are provided in Table S3 in the Supplementary Appendix. Patients in the intervention group were under deeper sedation than patients in the control group both during the 48-hour intervention period and on the third trial day (Fig. 2). During the first 24 hours, pa-tients in the intervention group had lower PEEP requirements than patients in the control group (between-group difference, −0.9 cm of water; 95% confidence interval [CI], −1.5 to −0.4). Dur-ing the first and second 24-hour periods, patients in the intervention group also had lower minute ventilation (the between-group difference on day 1 was −0.7 liters per minute [95% CI, −1.1 to −0.2], and on day 2, −0.8 liters per minute [95% CI, −1.2 to −0.4]), lower FIO2 requirements (the between-group difference on both day 1 and day 2 was −0.04 [95% CI, −0.06 to −0.02]), and higher driving pressures (the between-group difference on day 1 was 0.7 cm of water [95% CI, 0.0 to 1.3], and on day 2, 0.8 cm of water [95% CI, 0.1 to −1.5]). However, there were no between-group differences in the PaO2:FIO2 from day 1 through day 7. Improvement in oxygenation was similar among patients who were enrolled early and those who were enrolled late after the onset of ARDS. From day 1 through day 7, there was good adherence to the protocol with respect to PEEP and FIO2 recommendations, and adherence to recommended ventilation guidelines ranged from 80.1 to 87.5% with respect to low tidal vol-ume ventilation (≤6.5 ml per kilogram of predicted body weight) and 85.6 to 90.8% with respect to low plateau pressures (≤30 cm of water). The median daily fluid balance was 327 ml (interquar-tile range, −951 to 1456) on day 2 and −242 ml (interquartile range, −1432 to 728) on day 3, and there were no differences between trial groups. Additional details are provided in Figure S1 and Tables S4 through S8 in the Supplementary Ap-pendix.

Primary End PointAt 90 days, in-hospital death from any cause oc-curred in 213 patients (42.5%) in the interven-

tion group and in 216 patients (42.8%) in the control group (between-group difference, −0.3 percentage points; 95% CI, −6.4 to 5.9; P = 0.93) (Fig. 3 and Table 2). Treatment-by-subgroup inter-actions were not significant with respect to

Figure 2. Neuromuscular Blockade and Sedation.

Panel A shows the mean percentage of patients who received continuous neuromuscular blockade, and Panel B shows the mean percentage of patients who were under light sedation during the first week of the trial. Light sedation was defined by a score of 0 or −1 on the Richmond Agitation–Sedation Scale (scores range from 4 [combative] to −5 [unresponsive], with a score of 0 indicating that the patient is alert and calm), a score of 3 or 4 on the Riker Sedation–Agitation Scale (scores range from 1 [unresponsive] to 7 [dangerous agitation], with a score of 4 indicating that the patient is calm and cooperative), or a score of 2 or 3 on the Ramsay Sedation Scale (scores range from 1 [anxious, restless] to 6 [unresponsive], with a score of 2 indicating that the patient is cooperative and oriented).21-23 More details are provided in Tables S3 and S4 in the Supple-mentary Appendix. I bars indicate standard errors.

Perc

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NM

B

100

80

90

70

60

40

30

10

50

20

0First 48 Hr 48– 96 Hr >96 Hr

B Light Sedation

A NMB

Intervention group

Control group

Perc

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sun

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ight

Sed

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60

40

30

10

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Interventiongroup

Controlgroup

1 2 3 4 7



-48hr 48-96hr >96hrNMB群 97.4% 16.0% 12.7%

コントロール群 17.0% 7.9% 11.3%

投与期間

鎮静



a neuromuscular blocking agent during the first 48 hours at a median cisatracurium (or equivalent) dose of 38 mg (interquartile range, 14 to 200). Additional details on the dosing of neuromuscu-lar blocking agents are provided in Table S3 in the Supplementary Appendix. Patients in the intervention group were under deeper sedation than patients in the control group both during the 48-hour intervention period and on the third trial day (Fig. 2). During the first 24 hours, pa-tients in the intervention group had lower PEEP requirements than patients in the control group (between-group difference, −0.9 cm of water; 95% confidence interval [CI], −1.5 to −0.4). Dur-ing the first and second 24-hour periods, patients in the intervention group also had lower minute ventilation (the between-group difference on day 1 was −0.7 liters per minute [95% CI, −1.1 to −0.2], and on day 2, −0.8 liters per minute [95% CI, −1.2 to −0.4]), lower FIO2 requirements (the between-group difference on both day 1 and day 2 was −0.04 [95% CI, −0.06 to −0.02]), and higher driving pressures (the between-group difference on day 1 was 0.7 cm of water [95% CI, 0.0 to 1.3], and on day 2, 0.8 cm of water [95% CI, 0.1 to −1.5]). However, there were no between-group differences in the PaO2:FIO2 from day 1 through day 7. Improvement in oxygenation was similar among patients who were enrolled early and those who were enrolled late after the onset of ARDS. From day 1 through day 7, there was good adherence to the protocol with respect to PEEP and FIO2 recommendations, and adherence to recommended ventilation guidelines ranged from 80.1 to 87.5% with respect to low tidal vol-ume ventilation (≤6.5 ml per kilogram of predicted body weight) and 85.6 to 90.8% with respect to low plateau pressures (≤30 cm of water). The median daily fluid balance was 327 ml (interquar-tile range, −951 to 1456) on day 2 and −242 ml (interquartile range, −1432 to 728) on day 3, and there were no differences between trial groups. Additional details are provided in Figure S1 and Tables S4 through S8 in the Supplementary Ap-pendix.

Primary End PointAt 90 days, in-hospital death from any cause oc-curred in 213 patients (42.5%) in the interven-

tion group and in 216 patients (42.8%) in the control group (between-group difference, −0.3 percentage points; 95% CI, −6.4 to 5.9; P = 0.93) (Fig. 3 and Table 2). Treatment-by-subgroup inter-actions were not significant with respect to

Figure 2. Neuromuscular Blockade and Sedation.

Panel A shows the mean percentage of patients who received continuous neuromuscular blockade, and Panel B shows the mean percentage of patients who were under light sedation during the first week of the trial. Light sedation was defined by a score of 0 or −1 on the Richmond Agitation–Sedation Scale (scores range from 4 [combative] to −5 [unresponsive], with a score of 0 indicating that the patient is alert and calm), a score of 3 or 4 on the Riker Sedation–Agitation Scale (scores range from 1 [unresponsive] to 7 [dangerous agitation], with a score of 4 indicating that the patient is calm and cooperative), or a score of 2 or 3 on the Ramsay Sedation Scale (scores range from 1 [anxious, restless] to 6 [unresponsive], with a score of 2 indicating that the patient is cooperative and oriented).21-23 More details are provided in Tables S3 and S4 in the Supple-mentary Appendix. I bars indicate standard errors.

Perc

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NM

B

100

80

90

70

60

40

30

10

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0First 48 Hr 48– 96 Hr >96 Hr

B Light Sedation

A NMB

Intervention group

Control group

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1 2 3 4 7



NMB群• Deep sedation• RASS -4,-5 / RSS 5,6 / SAS 1,2

コントロール群• Light sedation• RASS 0,-1 / RSS 2,3 / SAS 3,4

ROSE Supplementary Material

13

Table S4. Daily 'on study' sedation parameters from baseline through study day 7

Study Richmond Agitation-Sedation Score Riker Sedation Agitation Scale

day Intervention Control Difference (95% CI) Intervention Control Difference (95% CI)

Baseline -3.2 ± 7.0 (407)

-2.6 ± 1.8 (406) - 2.3 ± 1.1 (79) 2.4 ± 1.1 (79) -

Day 1 -4.8 ± 0.8 (395) -2.7 ± 1.9 (402) -2.1 (-2.3, -1.9) 1.1 ± 0.4 (76) 2.4 ± 1.3 (73) -1.3 (-1.6, -1.0)

Day 2 - 4.6 ± 5.1 (376) -2.3 ± 2.0 (372) -2.3 (-2.9, -1.8) 1.3 ± 0.9 (75) 2.7 ± 1.3 (70) -1.4 (-1.8, -1.1)

Day 3 -2.9 ± 2.0 (361) -2.2 ± 2.0 (349) -0.7 (-1.0, -0.4) 2.4 ± 1.3 (68) 2.9 ± 1.3 (65) -0.5 (-1.0, -0.1)

Day 4 -2.7 ± 5.6 (341) - 2.0 ± 2.0 (332) -0.7 (-1.4, -0.1) 2.9 ± 1.3 (60) 2.8 ± 1.3 (62) 0.0 (-0.4, 0.5)

Day 5 -2.2 ± 2.0 (326) -1.8 ± 2.0 (310) -0.4 (-0.7, -0.1) 2.9 ± 1.3 (59) 2.9 ± 1.2 (57) 0.0 (-0.5, 0.5)

Day 6 -2.0 ± 2.0 (302) -1.6 ± 2.0 (291) -0.5 (-0.8, -0.2) 1.0 ± 13.9 (54) 3.1 ± 1.2 (51) -2.1 (-6.0, 1.8)

Day 7 -1.6 ± 2.1 (280) -1.5 ± 1.9 (257) -0.1 (-0.4, 0.3) 3.3 ± 1.5 (46) 3.1 ± 1.5 (50) 0.2 (-0.4, 0.8)

Plus-minus values are means ± SD with (no).

Richmond Agitation-Sedation Score with a range: +4 (combative) to -5 (unarousable), where 0 equals alert and calm.1 Riker Sedation Agitation Scale with a range: 1 (unarousable) to 7 (dangerous agitation), where 4 equals calm and cooperative]).2 Only 2 patients were managed with the Ramsay scale.

レスキュー

• 腹臥位：15%前後• リクルートメント⼿技：5%前後• ECMO：1%未満


20

Table S17. Organ failure free days

Organ failure free days by day 28 Intervention (N=501) Control (N=505) Difference (95% CI)

Any organ 12.4 ± 11.3 (n=480) 12.5 ± 11.5 (n=479) -0.1 (-1.5, 1.4)

Cardiovascular 16.8 ± 11.4 (n=493) 16.6 ± 11.7 (n=497) 0.2 (-1.3, 1.6)

Coagulation 17.5 ± 11.8 (n=499) 17.7 ± 11.8 (n=504) -0.2 (-1.7, 1.2)

Hepatic 17.9 ± 11.9 (n=471) 17.4 ± 11.9 (n=477) 0.6 (-1.0, 2.1)

Renal 15.3 ± 11.8 (n=499) 15.4 ± 11.9 (n=504) -0.1 (-1.6, 1.4)

Plus-minus values are means ± SD with (no.). We calculated the number of days without organ failure by subtracting the number of days with organ failure from the lesser of 28 days or the number of days to death if death occurred prior to day 29. Organs and systems were considered failure-free after patients were discharged from the hospital. For each organ, failure was defined as a sequential organ failure assessment (SOFA) score >2 (range: 0-4, where higher scores = greater dysfunction). No neurologic score was collected or assessed.11

Table S18. Use of adjunctive therapies

Day 0-2 Day 0-28

Characteristic Intervention Control Difference (95% CI) Intervention Control Difference (95% CI)

Any rescue therapy 93 (18.6) 90 (17.8) 0.7 (-4.0, 5.5) 130 (25.9) 125 (24.8) 1.2 (-4.2, 6.6)

Prone positioning 68 (13.6) 60 (11.9) 1.7 (-2.4, 5.8) 84 (16.8) 75 (14.9) 1.9 (-2.6, 6.4)

Inhaled epoprostenol 16 (3.2) 17 (3.4) -0.2 (-2.4, 2.0) 26 (5.2) 27 (5.3) -0.2 (-2.9, 2.6)

Recruitment maneuvers 14 (2.8) 16 (3.2) -0.4 (-2.5, 1.7) 29 (5.8) 30 (5.9) -0.2 (-3.1, 2.8)

Inhaled nitric oxide 4 (0.8) 12 (2.4) -1.6 (-3.1, 0.0) 7 (1.4) 17 (3.4) -2.0 (-3.8, -0.1)

ECMO 2 (0.4) 3 (0.6) -0.2 (-1.1, 0.7) 3 (0.6) 10 (2.0) -1.4 (-2.8, 0.0)

No. (%). Denominators are 501 and 505 in the intervention and control groups. ECMO denotes extracorporeal membrane oxygenation.

Table S19. Glucocorticoid use during the first week

Study day Overall Intervention Control Difference (95% CI)

Day 1 25.2% (244/970) 22.6% (109/482) 27.7% (135/488) -5.0% (-10.5%, 0.4%)

Day 2 24.2% (224/924) 22.7% (105/463) 25.8% (119/461) -3.1% (-8.7%, 2.4%)

Day 3 23.1% (207/897) 22.2% (101/455) 24.0% (106/442) -1.8% (-7.3%, 3.7%)

Day 4 21.1% (184/872) 20.6% (91/442) 21.6% (93/430) -1.0% (-6.5%, 4.4%)

Day 7 16.7% (130/778) 17.0% (67/395) 16.4% (63/383) 0.5% (-4.7%, 5.8%)

Percentage determined by N / available records.

Table S20. All-location mortality percentage estimates at study day 90 and day 365

Study day Intervention Control Difference (95% CI) P-value

Day 90 45.3 ± 2.2 45.3 ± 2.2 0.0 ± 3.1 0.99 Day 365 51.1 ± 2.2 51.1 ± 2.2 0.0 ± 3.2 0.98

The mortality percentages are the point estimates for days 90 and 365 taken from the non-parametric interval censored survival functions (see Statistical Analysis in the Methods section of the paper). P-value is calculated from a Z test.

酸素化・⼈⼯呼吸器

NMB群• PEEP：-0.9 (-1.5 to -0.4)• MV：-0.7 (-1.2 to -0.4)• FiO2：-0.04 (-0.06 to -0.02)• Driving pressure：0.7 (0.0 to 1.3)

P/Fは両群とも差がないARDS期間：早期 vs.晩期

酸素化の改善に差はない

プロトコール遵守率

• TV < 6.5ml/kg PBW• Pplat < 30cnH2O• 80-90%の患者で守られている


16

Table S8. Additional measures of 'on protocol' compliance

Measure Overall Intervention (N=501) Control (N=505) Difference (95% CI)

On target tidal volume * - % (No.)

Day 1 88.2 (n=457) 86.7 (n=428) 1.5 (-2.9, 5.9)

Day 2 88.5 (n=425) 85.9 (n=377) 2.5 (-2.1, 7.2)

Day 3 88.0 (n=366) 83.5 (n=303) 4.5 (-0.9, 9.8)

Day 4 83.6 (n=304) 83.6 (n=262) -0.0 (-6.2, 6.1)

Day 7 81.7 (n=164) 78.4 (n=148) 3.3 (-5.6, 12.2)

On target plateau pressure ◊ - % (No.)

Day 1 87.4 (n=382) 83.4 (n=331) 4.1 (-1.2, 9.3)

Day 2 89.1 (n=348) 84.8 (n=297) 4.2 (-1.0, 9.5)

Day 3 91.5 (n=282) 86.4 (n=221) 5.1 (-0.5, 10.6)

Day 4 92.8 (n=223) 85.9 (n=184) 7.0 (0.9, 13.0)

Day 7 92.2 (n=113) 89.2 (n=93) 3.0 (-5.2, 11.1)

Fluid balance - mL (No.)

Day 1 1136 [-109 - 2487] (n=964) 1310 [65-2716] (n=478) 956 [-208-2315] (n=486) 273 (-26, 572)

Day 2 327 [-951 - 1456] (n=918) 377 [-786 - 1532 (n=461) 304 [-1029 – 1383] (n=457) 116 (-153, 388)

Day 3 -242 [-1432 - 728] (n=889) -355 [-1478 – 700] (n=452) -169 [-1353 – 810] (n=537) -81 (-368, 206)

Day 4 -455 [-1539 - 620] (n=858) -576 [-1701 – 428] (n=438) -214 [-1387 – 970] (n=420) -369 (-623, -116)

Day 7 -301 [-1359 - 561] (n=7360 -330 [ -1395 – 532] (n=375) -274 [-1270 – 590] (n=361) 13 (-236., 262)

Cumulative fluid balance - mL (No.)

Day 1 2712 [611 - 5206] (n=970) 2678 [835 - 5569] (n=482) 2795 [365-4866] (n=488) 360 (-219, 939)

Day 2 2984 [-110 - 6206] (n=924) 3133 [33 - 6691] (n=463) 2741 [-319 – 5759] (n=461) 445 (-270, 1161)

Day 3 2260 [-1289 - 6255] (n=897) 2533 [-1074 – 6892] (n=455) 2014 [-1406 – 5768] (n=442) 482 (-362, 1326)

Day 4 1795 [-2103 - 6182] (n=872) 1804 [-2132 – 5992] (n=442) 1751 [-2083 – 6629] (n=430) 7 (-847, 1006)

Day 7 198 [-4389 - 5261] (n=778) 168 [-4297 – 5017] (n=395) 231 [-4568 – 5790] (n=383) -33 (-1173, 1106)

Reported as median and interquartile range, with number.

* Target tidal volume defined as <6.5 mL/kg ideal body weight. ◊ Target plateau pressure defined as <30 cmH2O.

⽔分バランス

• 両群に差はなし• Day1,2でプラスバランスだが、その後はマイナスへ


16




Day 1 88.2 (n=457) 86.7 (n=428) 1.5 (-2.9, 5.9)

Day 2 88.5 (n=425) 85.9 (n=377) 2.5 (-2.1, 7.2)

Day 3 88.0 (n=366) 83.5 (n=303) 4.5 (-0.9, 9.8)

Day 4 83.6 (n=304) 83.6 (n=262) -0.0 (-6.2, 6.1)

Day 7 81.7 (n=164) 78.4 (n=148) 3.3 (-5.6, 12.2)


Day 1 87.4 (n=382) 83.4 (n=331) 4.1 (-1.2, 9.3)

Day 2 89.1 (n=348) 84.8 (n=297) 4.2 (-1.0, 9.5)

Day 3 91.5 (n=282) 86.4 (n=221) 5.1 (-0.5, 10.6)

Day 4 92.8 (n=223) 85.9 (n=184) 7.0 (0.9, 13.0)

Day 7 92.2 (n=113) 89.2 (n=93) 3.0 (-5.2, 11.1)


Day 1 1136 [-109 - 2487] (n=964) 1310 [65-2716] (n=478) 956 [-208-2315] (n=486) 273 (-26, 572)

Day 2 327 [-951 - 1456] (n=918) 377 [-786 - 1532 (n=461) 304 [-1029 – 1383] (n=457) 116 (-153, 388)

Day 3 -242 [-1432 - 728] (n=889) -355 [-1478 – 700] (n=452) -169 [-1353 – 810] (n=537) -81 (-368, 206)

Day 4 -455 [-1539 - 620] (n=858) -576 [-1701 – 428] (n=438) -214 [-1387 – 970] (n=420) -369 (-623, -116)

Day 7 -301 [-1359 - 561] (n=7360 -330 [ -1395 – 532] (n=375) -274 [-1270 – 590] (n=361) 13 (-236., 262)


Day 1 2712 [611 - 5206] (n=970) 2678 [835 - 5569] (n=482) 2795 [365-4866] (n=488) 360 (-219, 939)

Day 2 2984 [-110 - 6206] (n=924) 3133 [33 - 6691] (n=463) 2741 [-319 – 5759] (n=461) 445 (-270, 1161)

Day 3 2260 [-1289 - 6255] (n=897) 2533 [-1074 – 6892] (n=455) 2014 [-1406 – 5768] (n=442) 482 (-362, 1326)

Day 4 1795 [-2103 - 6182] (n=872) 1804 [-2132 – 5992] (n=442) 1751 [-2083 – 6629] (n=430) 7 (-847, 1006)

Day 7 198 [-4389 - 5261] (n=778) 168 [-4297 – 5017] (n=395) 231 [-4568 – 5790] (n=383) -33 (-1173, 1106)




16




Day 1 88.2 (n=457) 86.7 (n=428) 1.5 (-2.9, 5.9)

Day 2 88.5 (n=425) 85.9 (n=377) 2.5 (-2.1, 7.2)

Day 3 88.0 (n=366) 83.5 (n=303) 4.5 (-0.9, 9.8)

Day 4 83.6 (n=304) 83.6 (n=262) -0.0 (-6.2, 6.1)

Day 7 81.7 (n=164) 78.4 (n=148) 3.3 (-5.6, 12.2)


Day 1 87.4 (n=382) 83.4 (n=331) 4.1 (-1.2, 9.3)

Day 2 89.1 (n=348) 84.8 (n=297) 4.2 (-1.0, 9.5)

Day 3 91.5 (n=282) 86.4 (n=221) 5.1 (-0.5, 10.6)

Day 4 92.8 (n=223) 85.9 (n=184) 7.0 (0.9, 13.0)

Day 7 92.2 (n=113) 89.2 (n=93) 3.0 (-5.2, 11.1)


Day 1 1136 [-109 - 2487] (n=964) 1310 [65-2716] (n=478) 956 [-208-2315] (n=486) 273 (-26, 572)

Day 2 327 [-951 - 1456] (n=918) 377 [-786 - 1532 (n=461) 304 [-1029 – 1383] (n=457) 116 (-153, 388)

Day 3 -242 [-1432 - 728] (n=889) -355 [-1478 – 700] (n=452) -169 [-1353 – 810] (n=537) -81 (-368, 206)

Day 4 -455 [-1539 - 620] (n=858) -576 [-1701 – 428] (n=438) -214 [-1387 – 970] (n=420) -369 (-623, -116)

Day 7 -301 [-1359 - 561] (n=7360 -330 [ -1395 – 532] (n=375) -274 [-1270 – 590] (n=361) 13 (-236., 262)


Day 1 2712 [611 - 5206] (n=970) 2678 [835 - 5569] (n=482) 2795 [365-4866] (n=488) 360 (-219, 939)

Day 2 2984 [-110 - 6206] (n=924) 3133 [33 - 6691] (n=463) 2741 [-319 – 5759] (n=461) 445 (-270, 1161)

Day 3 2260 [-1289 - 6255] (n=897) 2533 [-1074 – 6892] (n=455) 2014 [-1406 – 5768] (n=442) 482 (-362, 1326)

Day 4 1795 [-2103 - 6182] (n=872) 1804 [-2132 – 5992] (n=442) 1751 [-2083 – 6629] (n=430) 7 (-847, 1006)

Day 7 198 [-4389 - 5261] (n=778) 168 [-4297 – 5017] (n=395) 231 [-4568 – 5790] (n=383) -33 (-1173, 1106)



Primary end point



ARDS severity, ARDS duration, or previous neuro-muscular blockade use stratified according to hospital tercile. Other than the interaction of treatment assignment with ethnic group (P = 0.02 for interaction), no other interactions were sig-nificant (Fig. S2 and Tables S9 through S15 in the Supplementary Appendix).

Secondary End PointsAt 28 days, there was no between-group differ-ence in hospital mortality, days free of ventila-tion, days out of the ICU, or days out of the hospital (Table 2). Cardiovascular SOFA scores were higher in the intervention group than in the control group on day 1 (between-group differ-ence, 0.2; 95% CI, 0.1 to 0.4) and day 2 (between-group difference, 0.3; 95% CI, 0.1 to 0.5). How-ever, there were no differences thereafter, nor were there differences in total SOFA scores or other organ-specific SOFA scores. The use of adjunctive therapies appeared to be similar in the two groups during the 48-hour intervention period (between-group difference, 0.7 percentage

points; 95% CI, −4.0 to 5.5) and through day 28 (between-group difference, 1.2 percentage points; 95% CI, −4.2 to 6.6). Overall, prone positioning was used in 15.8% of patients (159 patients), with similar use in the two groups (between-group difference, 1.9 percentage points; 95% CI, −2.6 to 6.4). Most (56% [42 patients]) of the 75 patients who underwent prone positioning in the control group did not receive concomitant neuromuscular blockade. Glucocorticoid use was also similar in the two groups. The mean (±SE) estimated mortality at 1 year was also not different between groups (51.1±2.2% in the in-tervention group and 51.1±2.2% in the control group). Patient-reported outcomes were similar between the groups at 3, 6, and 12 months, in-cluding health-related scores and health-related limitations with respect to disability, cognitive function, symptoms resembling those of post-traumatic stress, and pain. Additional infor-mation on secondary end points is provided in Tables S16 through S23 in the Supplementary Appendix.

Figure 3. Patients Who Survived to Hospital Discharge and Were Discharged Home during the First 90 Days after Randomization.

The period of hospitalization included transfer to other health care facilities.

Perc

enta

ge o

f Pat

ient

s

100

80

90

70

60

40

30

10

50

20

00 908070605040302010

Day

Survivedto hospitaldischarge,

control group

Discharged to home,control group

Discharged to home,intervention group

Survived to hospitaldischarge,

intervention group



90⽇死亡率42.5% vs.42.8% (-0.3, -6.4 – 5.9)

• サブグループ解析でもほぼ同様の結果• ARDS重症度（P/F 120）• 割付までの時間（中央値）• 登録前NMB使⽤率での病院の層別化• 医師による取り下げ率での病院の層別化• 性別• ⼈種• ⺠族 P=0.015


10

Figure S2. Survival curves for the subgroups, PaO2 /FIO2 <120 and ≥120 mmHg

PaO2 denotes partial pressure of arterial oxygen, FIO2 denotes the fraction of inspired oxygen, and PaO2/FIO2 ratios expressed as mmHg. Data generated from Kaplan-Meier survival analysis, defining death as deaths occurring in-hospital, as per the primary outcome definition (see Methods). The cutoff values of <120 and ≥120 mmHg were pre-specified, based on a similar subgroup analysis in the ACURASYS study.10 There was no interaction between treatment assignment and subgroup (p=0.76, see Table S9).

Secondary end points

• 28⽇死亡率• 28⽇でのVFD/IFD/HFD• SOFA score



VariableIntervention Group


(N = 505)

Between-Group Difference (95% CI) P Value

percentage points

Primary end point: in-hospital death by day 90 — no. (%)†

213 (42.5±2.2) 216 (42.8±2.2) −0.3 (−6.4 to 5.9) 0.93


In-hospital death by day 28 — no. (%) 184 (36.7) 187 (37.0) −0.3 (−6.3 to 5.7)

Days free of ventilation at day 28‡ 9.6±10.4 9.9±10.9 −0.3 (−1.7 to 1.0)

Days not in ICU at day 28 9.0±9.4 9.4±9.8 −0.4 (−1.6 to 0.8)

Days not in hospital at day 28‡ 5.7±7.8 5.9±8.1 −0.2 (−1.1 to 0.8)

Safety end points

In-hospital recall of paralysis

Total no. of patients (%) 9 (1.8) 10 (2.0) −0.2 (−1.9 to 1.5)

Among patients who received neuromus-cular blockade — no./total no. (%)

9/487 (1.8) 2/129 (1.6) 0.3 (−2.1 to 2.7)

MRC score§

Day 7 46.7±14.4 49.5±12.3 −2.8 (−6.1 to 0.6)¶

Day 28 45.7±13.9 49.8±10.6 −4.1 (−9.0 to 0.9)¶

ICU-acquired weakness — no./total no. (%)∥

Day 7 50/122 (41.0) 41/131 (31.3) −9.7 (−21.5 to 2.1)

Day 28 22/47 (46.8) 14/51 (27.5) −19.4 (−38.2 to −0.6)

Any time through day 28 107/226 (47.3) 89/228 (39.0) −7.3 (−15.7 to 1.1)

Serious adverse events — no. of events** 35 22 0.09

Serious cardiovascular adverse events — no. of events**

14 4 0.02

Atrial fibrillation or SVT during ICU stay — no. (%)

101 (20.2) 99 (19.6) 0.88

Barotrauma — no. (%) 20 (4.0) 32 (6.3) 0.12

Pneumothorax on days 0 through 2 — no. (%) 8 (1.6) 10 (2.0) 0.81


* Unless otherwise indicated, plus–minus values are means ±SD. ICU denotes intensive care unit, and SVT supraventricular tachycardia.† Included are all deaths that occurred after randomization in any heath care facility before discharge home until day 90 of the trial. Patients

in a health care facility at day 91 were considered to be alive. The plus–minus values in this category are standard errors.‡ If in-hospital death occurred before day 29, the days free of ventilation and the days not in the hospital at day 28 were considered to be

zero.§ The Medical Research Council (MRC) scale was used to assess muscle strength in 6 muscle groups on each side of the body, for a total of

12 muscle groups. The score for each muscle group can range from 0 (no movement observed) to 5 (muscle contracts normally against full resistance), with the overall score ranging from 0 to 60.37 The MRC score at day 7 was assessed in 122 patients in the intervention group and 131 in the control group; the score at day 28 was assessed in 47 patients in the intervention group and 51 in the control group.

¶ The between-group difference is the difference in MRC score.∥ ICU-acquired weakness was defined as an MRC score of less than 48 if all 12 muscle groups were assessed, or a mean muscle-group

score of less than 4 when at least 7 of the 12 muscle groups were assessed.** A list of all adverse events is provided in Table S24 in the Supplementary Appendix. Participants may have had more than 1 adverse event.

Although mortality was high in both groups, only 1 death from complete heart block and refractory shock was considered possibly related to cisatracurium. No other deaths were reported by participating sites as possibly, probably, or definitely related to cisatracurium or any other procedure specified in the trial protocol.

Table 2. End Points.*




19

Table S16. Sequential Organ Failure Assessment (SOFA) scores SOFA score Change in SOFA score from baseline Intervention Control Difference (95% CI) Intervention Control Difference (95% CI) Coagulation

Baseline 0.9 ± 1.2 (488) 0.9 ± 1.2 (496) - - - - Day 1 1.0 ± 1.2 (468) 0.9 ± 1.2 (464) 0.1 (-0.1, 0.3) 0.1 ± 0.8 (468) 0.1 ± 0.8 (463) 0.0 (-0.1, 0.1) Day 2 1.1 ± 1.3 (459) 1.0 ± 1.2 (442) 0.1 (-0.1, 0.2) 0.2 ± 0.9 (459) 0.2 ± 1.9 (441) 0.0 (-0.1, 0.1) Day 3 1.0 ± 1.2 (434) 1.0 ± 1.2 (415) 0.0 (-0.1, 0.2) 0.1 ± 1.0 (434) 0.1 ± 1.0 (414) 0.0 (-0.1, 0.1) Day 4 1.0 ± 1.2 (417) 1.0 ± 1.2 (387) 0.1 (-0.1, 0.2) 0.1 ± 1.1 (417) 0.11.0 (386) 0.0 (-0.1, 0.2) Day 7 0.8 ± 1.2 (321) 0.7 ± 1.1 (297) 0.1 (-0.1, 0.3) -0.1 ± 1.2 (321) -0.2 ± 1.1 (296) 0.1 (-0.1, 0.3)

Liver Baseline 0.6 ± 1.1 (458) 0.6 ± 1.1 (467) - - - - Day 1 0.6 ± 1.1 (440) 0.6 ± 1.1 (437) 0.0 (-0.1, 0.2) 0.1 ± 0.5 (440) 0.1 ± 0.6 (436) 0.0 (-0.1, 0.1) Day 2 0.6 ± 1.1 (432) 0.6 ± 1.1 (415) 0.0 (-0.2, 0.1) 0.0 ± 0.5 (432) 0.1 ± 0.7 (414) -0.1 (-0.2, 0.0) Day 3 0.7 ± 1.2 (411) 0.7 ± 1.1 (391) 0.0 (-0.2, 0.1) 0.1 ± 0.7 (411) 0.1 ± 0.8 (390) -0.1 (-0.2, 0.1) Day 4 0.7 ± 1.2 (395) 0.7 ± 1.1 (366) 0.0 (-0.2, 0.2) 0.1 ± 0.8 (395) 0.2 ± 0.8 (365) 0.0 (-0.2, 0.1) Day 7 0.7 ± 1.2 (305) 0.7 ± 1.2 (282) 0.1 (-0.3, 0.1) 0.1 ± 0.8 (305) 0.2 ± 1.0 (281) -0.1 (-0.3, 0.0)

Cardiovascular Baseline 2.3 ± 1.6 (488) 2.5 ± 1.6 (496) - - - - Day 1 2.8 ± 1.5 (468) 2.5 ± 1.5 (464) 0.2 (0.1, 0.4) 0.5 ± 1.5 (468) 0.1 ± 1.3 (463) 0.4 (0.2, 0.6) Day 2 2.4 ± 1.5 (458) 2.1 ± 1.6 (442) 0.3 (0.1, 0.5) 0.2 ± 1.6 (458) -0.3 ± 1.6 (441) 0.5 (0.3, 0.7) Day 3 2.0 ± 1.5 (434) 1.8 ± 1.5 (415) 0.2 (0.0, 0.4) -0.2 ± 1.8 (434) -0.6 ± 1.7 (414) 0.3 (0.1, 0.6) Day 4 1.6 ± 1.5 (417) 1.5 ± 1.5 (386) 0.1 (-0.1, 0.3) -0.6 ± 1.8 (417) -0.9 ± 1.7 (385) 0.3 (0.0, 0.5) Day 7 1.1 ± 1.3 (321) 1.4 ± 1.4 (297) -0.2 (-0.4, 0.0) -1.1 ± 1.8 (321) -1.1 ± 1.8 (296) 0.0 (-0.2, 0.3)

Renal Baseline 1.6 ± 1.5 (488) 1.6 ± 1.6 (496) - - - - Day 1 1.6 ± 1.6 (468) 1.6 ± 1.6 (464) 0.0 (-0.2, 0.2) 0.0 ± 1.1 (468) 0.1 ± 1.1 (463) 0.0 (-0.2, 0.1) Day 2 1.6 ± 1.6 (459) 1.6 ± 1.6 (442) 0.0 (-0.2, 0.3) 0.0 ± 1.2 (459) 0.1 ± 1.2 (441) 0.0 (-0.2, 0.2) Day 3 1.7 ± 1.6 (434) 1.6 ± 1.7 (415) 0.1 (-0.1, 0.3) 0.1 ± 1.3 (434) 0.1 ± 1.2 (414) 0.1 (-0.1, 0.2) Day 4 1.6 ± 1.7 (417) 1.6 ± 1.7 (387) 0.0 (-0.2, 0.2) 0.0 ± 1.4 (417) 0.1 ± 1.4 (386) 0.0 (-0.2, 0.2) Day 7 1.6 ± 1.6 (321) 1.7 ± 1.7 (297) -0.1 (-0.3, 0.2) 0.0 ± 1.5 (321) 0.1 ± 1.5 (296) 0.0 (-0.3, 0.2)

Non-pulmonary SOFA Total Score (excluding neurologic) Baseline 5.5 ± 3.4 (488) 5.6 ± 3.4 (496) - - - - Day 1 6.0 ± 3.7 (468) 5.7 ± 3.6 (464) 0.4 (-0.1, 0.8) 0.7 ± 2.0 (468) 0.3 ± 2.0 (463) 0.4 (0.2, 0.7) Day 2 5.7 ± 3.9 (459) 5.3 ± 3.7 (442) 0.4 (-0.1, 0.9) 0.4 ± 2.3 (459) 0.0 ± 2.5 (441) 0.4 (0.1, 0.7) Day 3 5.3 ± 4.0 (434) 5.0 ± 3.7 (415) 0.3 (-0.2, 0.8) 0.1 ± 2.6 (434) -0.3 ± 2.7 (414) 0.3 (0.0, 0.7) Day 4 4.8 ± 4.2 (417) 4.6 ± 3.7 (387) 0.2 (-0.4, 0.7) -0.4 ± 2.8 (417) -0.6 ± 2.8 (386) 0.2 (-0.2, 0.6) Day 7 4.2 ± 3.7 (321) 4.4 ± 3.8 (297) -0.3 (-0.9, 0.3) -1.1 ± 3.0 (321) -1.0 ± 3.2 (296) 0.0 (-0.5, 0.5)

Plus-minus values are means ± SD (no.). Individual organ SOFA scores: range from 0 to 4, with higher scores indicative of worse organ dysfunction.11 Coagulation is based on platelet count, liver on total bilirubin, cardiovascular on mean arterial pressure and vasopressor utilization, and renal on creatinine and urine output. Total SOFA score is the sum of individual organ scores.

NMB control

Safety end points





(N = 505)


percentage points


213 (42.5±2.2) 216 (42.8±2.2) −0.3 (−6.4 to 5.9) 0.93






Safety end points




9/487 (1.8) 2/129 (1.6) 0.3 (−2.1 to 2.7)

MRC score§

Day 7 46.7±14.4 49.5±12.3 −2.8 (−6.1 to 0.6)¶

Day 28 45.7±13.9 49.8±10.6 −4.1 (−9.0 to 0.9)¶


Day 7 50/122 (41.0) 41/131 (31.3) −9.7 (−21.5 to 2.1)

Day 28 22/47 (46.8) 14/51 (27.5) −19.4 (−38.2 to −0.6)




14 4 0.02


101 (20.2) 99 (19.6) 0.88

Barotrauma — no. (%) 20 (4.0) 32 (6.3) 0.12













Safety end points





(N = 505)


percentage points


213 (42.5±2.2) 216 (42.8±2.2) −0.3 (−6.4 to 5.9) 0.93






Safety end points




9/487 (1.8) 2/129 (1.6) 0.3 (−2.1 to 2.7)

MRC score§

Day 7 46.7±14.4 49.5±12.3 −2.8 (−6.1 to 0.6)¶

Day 28 45.7±13.9 49.8±10.6 −4.1 (−9.0 to 0.9)¶


Day 7 50/122 (41.0) 41/131 (31.3) −9.7 (−21.5 to 2.1)

Day 28 22/47 (46.8) 14/51 (27.5) −19.4 (−38.2 to −0.6)




14 4 0.02


101 (20.2) 99 (19.6) 0.88

Barotrauma — no. (%) 20 (4.0) 32 (6.3) 0.12













• ⿇痺の記憶：1.8% vs. 2%(-0.2(-1.9 – 1.5))• MRC・ICU-AW：有意差はないがNMBで低め・⾼め

• ⼼⾎管イベントはNMB群で多い：14 vs.4 (p=0.02)

• Barotrauma：4% vs 6.3% p=0.12• 気胸 Day0-7： 2.8% vs 5% p=0.10

Safety end points

•両群とも死亡率は⾼いが、cisatracuriumが関連する死亡は１例のみ•⾦縛りの頻度は低い• NMB群で6⽇⽬までの⾝体活動度は低い• MRC/ICU-AWも差はないが、半数以上が週１の筋⼒評価ができていない•⼼⾎管イベントはNMB群で多い• Barotrauma・気胸は両群で変わらず


21

Table S21. Outcomes at 3 months

Characteristic Intervention Control Difference (95% CI)

Assessments

EQ-5D-5L * 0.66 ± 0.41 (n=207) 0.73 ± 0.39 (n=194) 0.0 (-0.1, 0.1)

Difficulty in a daily activity - no./available records (%) ◊

168/212 (79.2) 154/196 (78.6) 0.7 (-7.3, 8.6)

Disability Score † 3.3 ± 2.7 (n=212) 3.0 ± 2.7 (n=196) 0.3 (-0.3, 0.8)

Self-rated Health ‡ 3.4 ± 1.1 (n=164) 3.3 ± 1.0 (n=158) 0.1 (-0.1, 0.3)

Pain Interference § 2.6 ± 1.4 (n=162) 2.6 ± 1.4 (n=157) 0.0 (-0.3, 0.3)

PTSS - no. (%) ^ - -

MoCA blind " 22.2 ± 5.2 (n=154) 22.8 ± 4.8 (n=133) -0.6 (-1.7, 0.6)

AD8 scores # 3.1 ± 2.8 (n=45) 2.5 ± 2.6 (n=37) 0.6 (-0.6, 1.8)

Other outcomes - no./available records (%)

Location of residence % home 173/212 (81.6) 161/195 (82.6) -1.0 (-8.4, 6.5)

Hospital readmission 69/211 (32.7) 63/195 (32.3) 0.4 (-8.7, 9.5)

ER visit 46/211 (21.8) 32/195 (16.4) 5.4 (-2.2, 13.0)

Return to work - no./available records (%) 32/212 (15.1) 34/196 (17.3) -2.3 (-9.4, 4.9)

Significant change in work duties 77/119 (64.7) 68/107 (63.6) 1.2 (-11.4, 13.7)

Impact on daily activities - no. (%) (n=246) (n=238)

Eating 45 (18.3) 36 (15.1) 3.2 (-3.5, 9.8)

Getting in or out of bed 93 (37.8) 84 (35.3) 2.5 (-6.1, 11.1)

Using the toilet 82 (33.3) 66 (27.7) 5.6 (-2.6, 13.8)

Preparing a hot meal 67 (27.2) 66 (27.7) -0.5 (-8.5, 7.5)

Making phone calls 43 (17.5) 37 (15.5) 1.9 (-4.7, 8.5)

Taking medications 49 (19.9) 44 (18.5) 1.4 (-5.6, 8.4)

Managing money 40 (16.3) 46 (19.3) -3.1 (-9.9, 3.7)

Shopping for groceries 97 (39.4) 87 (36.6) 2.9 (-5.8, 11.5)

Stooping, kneeling or crouching 154 (62.6) 158 (66.4) -3.8 (-12.3, 4.7)

Lifting/carrying weights >10 pounds 145 (58.9) 139 (58.4)

Plus-minus values are means ± SD. * The EQ-5D-5L ranges from -0.109 to 1; higher scores indicate better quality of life, with less than 0 a state assessed by

general population norms to be worse than death and 1 indicating good health.5 ◊ Difficulty in a daily activity is the percentage reporting any difficulty in any of the 10 Katz Activity of Daily Living (ADL),

Lawton Instrumental Activities of Daily Living (IADL), or Nagi scale items asked.6 † The Disability score ranges from 0 to 10 and is the number of those 10 ADL/IADL/Nagi items on which the respondent or

their proxy reported difficulty due to health conditions, with higher scores representing worse disability, and scores of 4 or greater interpretable as representing severe disability.6

‡ Self-rated health was a five-point categorical score with 1 indicating excellent health and 5 indicating poor health. § Pain interference was a five-point categorical score with 1 indicating no interference with one’s daily life and 5 indicating

extreme interference. ^ The PTSS-14 ranges from 14 to 98, with higher scores indicate more symptoms, and with scores above 45 indicating a

threshold for a higher likelihood of post-traumatic stress-like symptoms.7 " MOCA Blind score measures cognition where the individual themselves can be tested, ranging up to 30; scores above 26 are

considered the normal range for cognition.8 # AD8 scores are used to assess cognition by proxies for the subset of patients alive but not able to respond themselves; AD8

scores range 0 to 8, with high scores suggesting worse cognitive function and scores greater than 2 indicating that cognitive impairment is likely to be present.9

3,6,12ヶ⽉後の患者調査報告でも有意差なし

DISCCUSION

本研究では…

•プロトコールの遵守率が⾼い• コントロール群のNMB使⽤が最⼩限• 呼吸器設定• 輸液⽅法

•サブグループ解析も同様の結果• 重症度• Onset time• Trial siteをNMB使⽤の有無での分別

• 90⽇死亡率が改善しなかった理由• 両群ともHigh PEEPで設定

Moderate-severe ARDSに対するARDSの有⽤性

NMB⾃体の効果が薄れた

• コントロール群は浅い鎮静レベルで管理浅鎮静での管理で予後が改善

NMB群は深鎮静の影響で低⾎圧・徐脈が多い

JAMA 2010;303:865-73.

Am J Respir Crit Care Med 2012;186:724-31. Crit Care Med 2018; 46:850-9.

• 90⽇死亡率が改善しなかった理由• 腹臥位管理：15.8% vs. 30% (ACURASYS)

16時間以上の腹臥位による管理で予後を改善

⼀般的な割合だが、ACURASYSで腹臥位が多い

• 発症〜登録までの時間(中央値)：7.6hr vs. 16hr (ACURASYS)→早期に死亡してしまう症例が含まれた可能性→早期に改善する予後のいいARDSが含まれた可能性

N Engl J Med 2013; 368:2159-68.

Rapidly Improving ARDS in Therapeutic Randomized Controlled Trials CHEST 2019; 155:474-482

• ARDS networkの6研究を⽤いて2次解析• riARDS：登録初⽇で抜管 or P/F >300

derivation dataset and 0.76 (95% CI, 0.69-0.83) in thevalidation dataset (Table 3).

DiscussionThis secondary analysis of patient-level data from theARDSNet trials suggests that not only is riARDScommon but also that its prevalence has increased overtime. It had distinct characteristics and was strongly andconsistently associated with better outcomes comparedwith ARDS > 1 day, with differences in mortality andnonpulmonary organ failure-free days. PaO2:FIO2 atscreening, change in PaO2:FIO2 from screening toenrollment, usage of vasopressor agents, FIO2 atenrollment, and serum bilirubin levels were usefulvariables for prediction of riARDS.

We found that riARDS was common. When estimatingits prevalence, one should keep in mind that, given thelack of a gold standard, ARDS is a challenging diagnosisto make.7 One could therefore support that patients withriARDS had an alternate noninflammatory cause ofhypoxemia and bilateral opacities (eg, atelectasis,cardiogenic pulmonary edema) that could be easilyreversed.26-29 This theory would explain both their rapid

recovery and better overall outcomes (Fig 2, Table 2).However, all patients included in this secondary analysismet the consensus definition criteria of ARDS and wereenrolled in high-quality, randomized controlledtherapeutic trials.17-19

Our finding that the prevalence of riARDS increasedover time is intriguing. One could wonder whether thisfinding is due to differences in exclusion criteria ofARDSNet trials.14-19 For example, although in theARMA and ALVEOLI trials14,15 patients were excludedif clinicians-investigators were unwilling to use volumeassist control for at least 12 h, this exclusion criterionwas dropped in later trials,16-19 and any mode ofventilation (including pressure support) was allowed.One could also attribute the temporal trends inprevalence of riARDS to the fact that optimal ICUpractices, based in part on earlier ARDSNet studies,14,16

were more likely applied in more recent than earliertrials. For example, lung protective ventilation andconservative fluid strategies, as well as sedation cessationpolicies and spontaneous breathing trials, may currentlybe more prevalent than previously, a fact that may helpprevent ventilator-induced lung injury and decreaseduration of mechanical ventilation.3,16,30 There has also

TABLE 2 ] Outcomes of Patients With Rapidly Improving ARDS vs ARDS> 1 Day

OutcomeRapidly ImprovingARDS (n ¼ 265) ARDS > 1 Day (n ¼ 1,644) P Value

60-d mortality 27 (10.2) 433 (26.3) < .0001

Ventilator-free days 27 (24-27) 18 (0-23) < .0001

ICU-free days 24 (21-26) 16 (0-21) < .0001

Nonpulmonary organ failure-free days 25 (4-27) 15 (0-25) < .0001

Data are presented as No. (%) or median (interquartile range). Patients discharged from the hospital with unassisted breathing before 60 days wereconsidered to be alive at 60 days. Ventilator-free days, ICU-free days, and nonpulmonary organ failure-free days were calculated by the number of days inthe first 28 days that a patient was alive and not on a ventilator, not in the ICU, or free of nonpulmonary organ failure, respectively.

TABLE 3 ] Logistic Regression Model for Predicting Rapidly Improving ARDS at Trial Enrollment

Variable

Univariate Analysis Multivariate Analysis

OR (95% CI) P Value OR (95% CI) P Value

PaO2:FIO2 at screeninga 1.05 (1.03-1.08) < .0001 1.08 (1.04-1.12) < .0001

Change in PaO2:FIO2 fromscreening to enrollmenta

1.10 (1.07-1.12) < .0001 1.10 (1.07-1.13) < .0001

No use of vasopressoragents (vs yes)

1.73 (1.19-2.52) .004 1.60 (1.06-2.43) .025

FIO2 # 0.45 5.56 (3.75-8.24) < .0001 2.97 (1.90-4.64) < .0001

Bilirubin 0.83 (0.71-0.98) .024 0.81 (0.67-0.98) .027

The area under the receiver-operating curve of the model for predicting rapidly improving ARDS was 0.82 (95% CI, 0.78-0.85) (negative predictive value,97%; positive predictive value, 29%; specificity, 69%; sensitivity, 85%) in the derivation dataset and 0.76 (95% CI, 0.69-0.83) (negative predictive value,93%; positive predictive value, 26%; specificity, 70%; sensitivity, 68%) in the validation dataset.aReported as per 10 point difference.

chestjournal.org 479

The primary outcome of the present study was 60-day mortality, withpatients discharged from the hospital with unassisted breathing priorto 60 days considered to be alive at 60 days. Time to mortality wasestimated for riARDS and ARDS > 1 day according to Kaplan-Meier analysis and compared by using log-rank tests. We furthertested the association between riARDS and the primary outcomewith a Cox proportional hazards regression, estimating the odds ofmortality within 60 days and using riARDS status as the maincovariate. The analysis corrected for severity of illness by using theAPACHE III score, PaO2:FIO2 at enrollment, and individual trialassignment. Secondary outcomes included the number of days in thefirst 28 days that a patient was alive and not on a ventilator(ventilator-free days), not in the ICU (ICU-free days), or free ofnonpulmonary organ failure (nonpulmonary organ failure-free days).These secondary outcomes have been consistently used in theliterature.4,5,19,25 For each individual trial, both the primary andsecondary outcomes were also compared across experimentaltreatment groups among patients with riARDS and ARDS > 1 day.

We attempted to identify which variables are important to predictriARDS as early as the time of trial enrollment (when patients wereventilated according to a standardized ARDS Clinical Trials Networklower tidal-volume protocol using positive end-expiratory pressure[PEEP]:FIO2 tables).17-19 We randomly divided patients with fullclinical data enrolled in the three most recently published ARDSNet

trials (ALTA, EDEN, and SAILS) into a training and a validationdataset. Machine learning techniques were then used to analyze alarge number of individual variables that were associated withriARDS in the derivation dataset. Random forests were used for thepredictive variables based on level of importance for riARDS status,and the top variables were selected for further study. A final set ofpredictive variables was determined by using insights from themachine learning techniques as well as clinical expertise to optimizesensitivity and negative predictive value. A logistic regression modelwas then created based on these selected variables to quantify theindependent effect of each variable in a parametric model.Multicollinearity of the model was explored by using correlation andvariance inflation factors, with a variance inflation factor > 2considered problematic. We measured accuracy of the logistic modelwith area under the receiver-operating curve, then dichotomized it atthe Youden optimal point and estimated sensitivity, specificity,and negative and positive predicted values, with 95% CIs for each.The logistic model was then used to predict riARDS in thevalidation dataset, to this point unused. Further details are availablein e-Appendix 1, Methods.

All statistical analyses were conducted by using R statistical softwareversion 3.2.3 (R Foundation for Statistical Computing). All P valueswere two-sided, and statistical significance was considered at ana level of 0.05.

Results

Prevalence of riARDS

Of the 4,361 unique patients enrolled in the randomizedcontrolled trials,14-19 458 (10.5%) no longer met thecriteria for ARDS on the first study day followingenrollment. The proportion of enrolled subjects classifiedas riARDS increased over time, from a prevalence of7.3% in ARMA14 to 15.2% in SAILS19 (r2 ¼ 0.760;P ¼ .024) (Fig 1). The association between year of study

publication and riARDS status remained whenaccounting for study-wide ventilator practice, number ofdays from diagnosis of ARDS to trial enrollment, andpatient-level APACHE III scores (adjusted OR, 1.08;95% CI, 1.04-1.13; P ¼ .0003) (e-Table 2).

Due to the increasing prevalence of riARDS over time(Fig 1) and to better reflect modern clinical practice,the remainder of our analyses considered only datafrom the three most recently published ARDSNettrials; namely, ALTA, EDEN, and SAILS (all publishedafter 2010).17-19 Of the 1,909 patients in these trials,197 (10.3%) were extubated on the first study day, and265 (13.9%) patients in total met our definition ofriARDS (Table 1).9

Baseline Characteristics

Baseline data are summarized in Table 1. Use ofvasopressor agents was less common (98 of 265 [37.0%]vs 867 of 1,644 [52.7%]; P < .001), and APACHE IIIscores were lower (80 [64-100] vs 92 [73-112]; P < .001)in patients with riARDS compared with ARDS > 1 day.Pneumonia as the primary risk factor was less commonin patients with riARDS than with ARDS > 1 day (147of 265 [55.5%] vs 1,066 of 1,644 [64.8%]; P ¼ .004]. Riskfactors did not differ between mild, moderate, andsevere ARDS (e-Table 3).

The compared groups differed in severity according tothe Berlin definition,9 with patients with riARDS morelikely to have mild or moderate disease than severe

0%

2000 2005Publication Year

2010 2015

5%

10%

15%

20%

ARMA FACTT

EDEN

SAILS

Alveoli

ALTA

Pat

ient

s W

ith R

apid

ly Im

prov

ing

AR

DS

Figure 1 – Prevalence of rapidly improving ARDS over time. Each circlerepresents an ARDS Network trial, and circle size is proportional tostudy sample size. Increase in prevalence of rapidly improving ARDSover time was statistically significant. ALTA ¼ Albuterol for theTreatment of Acute Lung Injury; ALVEOLI ¼ Assessment of Low TidalVolume and Elevated End-expiratory Volume to Obviate Lung Injury;ARMA ¼ Acute Respiratory Distress Syndrome (ARDS) Clinical TrialsNetwork Low-Tidal-Volume (VT) Trial; EDEN ¼ Early vs DelayedEnteral Nutrition; FACTT ¼ Fluid and Catheter Treatment Trial;SAILS ¼ Statins for Acutely Injured Lungs from Sepsis.

476 Original Research [ 1 5 5 # 3 CHES T MA R C H 2 0 1 9 ]

6 studies, 4361 patientsü 458(10.5%)がriARDS

ü 予後も良好60⽇死亡率：10.2% vs.26.3%

• 発症〜登録までの時間(中央値)：7.6hr vs. 16hr(ACURASYS)→早期に改善する予後のいいARDSが含まれた可能性

• 割付前にP/F>200に改善した症例は除外

• Onset timeを中央値の前後で分けて層別解析→結果はPrimary end pointと同様


17

Table S9. Day 90 mortality percentage stratified by PaO2/FIO2 ratio

PaO2/FIO2 ratio Intervention Control Difference (95% CI) P-value

PaO2/FIO2 <120 mmHg (N=720) 42.5 ± 2.6 (362) 42.2 ± 2.6 (358) 0.4 (-6.9, 7.6)

PaO2/FIO2 >120 mmHg (N=286) 42.4 ± 4.2 (139) 44.2 ± 4.1 (147) -1.8 (-13.3, 9.7)

Interaction 2.1 (-11.4, 15.7) 0.76

Mortality percentage - (# of patients who died/# of patients enrolled) x 100 ± StdErr (no.). P-value calculated from Wald test.

Table S10. Day 90 mortality percentage stratified by duration of ARDS prior to randomization

ARDS to randomization time Intervention Control Difference (95% CI) P-value

< median (N=503) 40.5 ± 3.2 (232) 44.6 ± 3.0 (271) -4.1 (-12.8, 4.5)

> median (N=503) 44.2 ± 3.0 (269) 40.6 ± 3.2 (234) 3.6 (-5.0, 12.3)

Interaction -7.8 (-20.0, 4.5) 0.21

Time measured from first documentation of moderate-to-severe ARDS until randomization. The overall median time was 7.6 hours. The median time for the cohort above the median was 15.6 hours, and that for those below the median was 3.7 hours. Mortality percentage - (# of patients who died/# of patients enrolled) x 100 ± StdErr (no.). P-value is calculated from Wald test.

Table s11. Day 90 mortality percentage stratified by hospital tercile for prior NMB use

Tercile # hospitals; patients Exclusion rate Intervention Control Difference (95% CI)

#1 16; 443 9.2% 38.1 ± 3.3 (223) 40.0 ± 3.3 (220) -1.9 (-11.0, 7.2)

#2 16; 375 25.7% 50.3 ± 3.7 (185) 45.8 ± 3.6 (190) 0.045 (-5.6, 14.6)

#3 16; 188 61.1% 37.6 ± 5.0 (93) 43.2 ± 5.1 (95) -5.5 (-19.5, 8.5)

Interaction P-Value: 0.47

NMB denotes neuromuscular blockade. Mortality percentage - (# of patients who died/# of patients enrolled) x 100 ± StdErr

(no.). P-value is calculated from Wald test. Exclusion rate is the summed rate of patients excluded for prior NMB use/enrolled

plus excluded for prior NMB use, weighted by sites' enrollment numbers.

Table S12. Day 90 mortality percentage estimates stratified by gender

Characteristic Intervention Control Difference (95% CI) P-value

Male (N=560) 42.6 ± 2.9 (291) 44.2 ± 3.0 (269) -1.6 (-9.8, 6.6)

Female (N=446) 42.4 ± 3.4 (210) 41.1 ± 3.2 (236) 1.3 (-7.9, 10.4)

Interaction -2.9 (-15.2, 9.4) 0.644

Mortality percentage - (# of patients who died/# of patients enrolled) x 100 ± StdErr (no.). P-value is calculated from Wald test.

Table S13. Day 90 mortality percentage estimates stratified by race


Non-White (N=168) 47.4 ± 5.7 (76) 38.0 ± 5.1 (92) 9.3 (-5.7, 24.3)

White (N=705) 41.6 ± 2.6 (361) 43.3 ± 2.7 (344) -1.8 (-9.1, 5.5)

Interaction 11.1 (-5.6, 27.8) 0.192

Mortality percentage - (# of patients who died/#of patients enrolled) x 100 ± StdErr (no.). P-value is calculated from Wald test.

Limitation

•除外理由で多いもの＝登録前のNMBの使⽤→臨床医がNMBが有効な症例と判断した可能性

除外がほとんどない施設に限って解析→結果はPrimary end pointと同様


17

Table S9. Day 90 mortality percentage stratified by PaO2/FIO2 ratio

PaO2/FIO2 ratio Intervention Control Difference (95% CI) P-value

PaO2/FIO2 <120 mmHg (N=720) 42.5 ± 2.6 (362) 42.2 ± 2.6 (358) 0.4 (-6.9, 7.6)

PaO2/FIO2 >120 mmHg (N=286) 42.4 ± 4.2 (139) 44.2 ± 4.1 (147) -1.8 (-13.3, 9.7)

Interaction 2.1 (-11.4, 15.7) 0.76

Mortality percentage - (# of patients who died/# of patients enrolled) x 100 ± StdErr (no.). P-value calculated from Wald test.

Table S10. Day 90 mortality percentage stratified by duration of ARDS prior to randomization

ARDS to randomization time Intervention Control Difference (95% CI) P-value

< median (N=503) 40.5 ± 3.2 (232) 44.6 ± 3.0 (271) -4.1 (-12.8, 4.5)

> median (N=503) 44.2 ± 3.0 (269) 40.6 ± 3.2 (234) 3.6 (-5.0, 12.3)

Interaction -7.8 (-20.0, 4.5) 0.21

Time measured from first documentation of moderate-to-severe ARDS until randomization. The overall median time was 7.6 hours. The median time for the cohort above the median was 15.6 hours, and that for those below the median was 3.7 hours. Mortality percentage - (# of patients who died/# of patients enrolled) x 100 ± StdErr (no.). P-value is calculated from Wald test.

Table s11. Day 90 mortality percentage stratified by hospital tercile for prior NMB use

Tercile # hospitals; patients Exclusion rate Intervention Control Difference (95% CI)

#1 16; 443 9.2% 38.1 ± 3.3 (223) 40.0 ± 3.3 (220) -1.9 (-11.0, 7.2)

#2 16; 375 25.7% 50.3 ± 3.7 (185) 45.8 ± 3.6 (190) 0.045 (-5.6, 14.6)

#3 16; 188 61.1% 37.6 ± 5.0 (93) 43.2 ± 5.1 (95) -5.5 (-19.5, 8.5)

Interaction P-Value: 0.47

NMB denotes neuromuscular blockade. Mortality percentage - (# of patients who died/# of patients enrolled) x 100 ± StdErr

(no.). P-value is calculated from Wald test. Exclusion rate is the summed rate of patients excluded for prior NMB use/enrolled

plus excluded for prior NMB use, weighted by sites' enrollment numbers.

Table S12. Day 90 mortality percentage estimates stratified by gender


Male (N=560) 42.6 ± 2.9 (291) 44.2 ± 3.0 (269) -1.6 (-9.8, 6.6)

Female (N=446) 42.4 ± 3.4 (210) 41.1 ± 3.2 (236) 1.3 (-7.9, 10.4)

Interaction -2.9 (-15.2, 9.4) 0.644

Mortality percentage - (# of patients who died/# of patients enrolled) x 100 ± StdErr (no.). P-value is calculated from Wald test.

Table S13. Day 90 mortality percentage estimates stratified by race


Non-White (N=168) 47.4 ± 5.7 (76) 38.0 ± 5.1 (92) 9.3 (-5.7, 24.3)

White (N=705) 41.6 ± 2.6 (361) 43.3 ± 2.7 (344) -1.8 (-9.1, 5.5)

Interaction 11.1 (-5.6, 27.8) 0.192

Mortality percentage - (# of patients who died/#of patients enrolled) x 100 ± StdErr (no.). P-value is calculated from Wald test.

Limitation

•呼吸器との⾮同調を評価していない→ NMB使⽤することで本質的には同調できる

•医療者は盲検化されていない→短期での筋⼒評価・活動性評価・合併症の短期的な評価に影響した可能性

Crit Care Med 2018;46(2):e151- e157.

CONCLUSION

• Moderate〜severe ARDS (P/F < 150) に対して

•早期にcisatracuriumを持続投与することは

•⾼PEEP・浅鎮静で管理するのと⽐べて

• 90⽇死亡率は低下させない

• ACURASYSが広まらない理由• 介⼊群の死亡率が低下する理由が明確でない• 2⽇間の投与で、死亡率が18⽇⽬から差が出る• VILIやbiotraumaが減るとされるが、確証はなし• NMB投与によるICU-AWの懸念

E d i t o r i a l



Early Paralytic Agents for ARDS? Yes, No, and Sometimes

Arthur S. Slutsky, C.M., M.D., and Jesús Villar, M.D., Ph.D.

Lung-protective ventilation, which includes low tidal volumes and limitation of plateau pressures, is the standard approach in patients with acute respiratory distress syndrome (ARDS).1 Almost a decade ago, the ARDS et Curarisation Systema-tique (ACURASYS) trial2 showed that in patients with moderate-to-severe ARDS, a strategy of 48 hours of deep sedation with muscle paralysis induced by an intravenous infusion of cisatracu-rium resulted in a lower incidence of barotrauma and higher adjusted overall survival at 90 days than deep sedation alone. These results were un-expected, since the intervention was performed only for the first 2 days, yet the Kaplan–Meier survival curves were virtually superimposable for about 18 days before they separated. The reason for the lower mortality in the intervention group was uncertain, but it was thought to be because the use of cisatracurium led to decreased venti-lator-induced lung injury and biotrauma (i.e., the release of mediators in the lung and transloca-tion of these mediators into the systemic circu-lation).3,4 Perhaps because of this uncertainty, along with concerns about long-term neuromus-cular function after treatment with cisatracurium, the addition of a paralytic agent to a lung-pro-tection strategy was not widely adopted by the critical care community.

For these reasons, and because current clini-cal practice has changed since the ACURASYS trial was conducted, the Reevaluation of Sys-temic Early Neuromuscular Blockade (ROSE) trial was performed to reexamine the benefits of cisatracurium-induced paralysis in patients early after the onset of ARDS. Patients with moderate-to-severe ARDS were assigned either to a 48-hour continuous infusion of cisatracurium with deep

sedation or to a usual-care approach with light sedation and without routine neuromuscular blockade. The trial, the results of which are now reported in the Journal,5 was stopped early for futility. The results were markedly different from those of the ACURASYS trial. In the ROSE trial, there was no between-group difference in the number of patients with barotrauma, and mor-tality at 90 days was virtually identical in the two groups (42.5% of patients in the intervention group and 42.8% in the control group died).

Why should the results of two well-performed trials differ so greatly? As shown in Table 1, there were a number of differences between the trials that could plausibly explain the different results. However, we postulate that one of these factors — the difference in sedation levels — is the major reason. Many patients who are admit-ted to an intensive care unit receive some seda-tion to treat anxiety or agitation and to facilitate care. Deeper sedation is also often used when the patient is “fighting the ventilator” (so-called patient–ventilator dyssynchrony). Dyssynchrony is common during mechanical ventilation and is associated with prolonged duration of mechani-cal ventilation and increased mortality.6

In 2013, Akoumianaki et al.7 identified a pre-viously unrecognized form of dyssynchrony in patients with ARDS. They called this dyssyn-chrony reverse triggering, because a breath de-livered by the ventilator triggered a contraction of the diaphragm, which initiated a spontaneous breath — the reverse of what happens during assisted ventilation. Because the second breath can occur before a complete exhalation, the pa-tient can receive a much larger tidal volume (called breath stacking) than with the initial ven-



Neuromuscular Blocking Agents in ARDS

n engl j med 363;12 nejm.org september 16, 2010 1113

The incidence of ICU-acquired paresis, as evaluated on the basis of the MRC score on day 28 or at the time of ICU discharge, did not differ significantly between the two groups (Table 3).

Secondary Post Hoc OutcomeCorticosteroids were used during the ICU stay in 189 patients. There was no significant effect of cisatracurium use on the 90-day mortality in the subgroup of patients given corticosteroids (Fig. 6 in the Supplementary Appendix).

Ventilator Settings and Lung FunctionVentilator settings and lung-function variables dur-ing the first week are given in Table 7 in the Sup-plementary Appendix. On day 7, the PaO2:FiO2 ratio was higher, and the PaCO2 value lower, in the cisatracurium group than in the placebo group.

CointerventionsDuring the ICU stay, there were no significant between-group differences in the incidence of cointerventions. A total of 42% of patients in the cisatracurium group and 48% in the placebo group were treated with the use of prone positioning, inhaled nitric oxide, intravenous almitrine mesy-late, or a combination of these (Table 8 in the Sup-plementary Appendix). The criteria for using these interventions were the same in the two groups.

Open-label cisatracurium was given more fre-quently in the placebo group than in the cisatra-cu rium group during the first 48 hours after enrollment. However, the two groups did not dif-fer significantly with respect to the number of pa-tients given at least one open-label cisatracuri um bolus during the entire ICU stay after enrollment (Table 8 in the Supplementary Appendix). The re-quired dose of sedatives or analgesics was similar in the two groups during the first week of the study (Table 9 in the Supplementary Appendix).

SafetyBradycardia developed during the cisatracurium infusion in one patient. No other side effects were reported.

Discussion

Treatment with the neuromuscular blocking agent cisatracurium for 48 hours early in the course of severe ARDS improved the adjusted 90-day sur-vival rate, increased the numbers of ventilator-free days and days outside the ICU, and decreased

the incidence of barotrauma during the first 90 days. It did not significantly improve the overall 90-day mortality.

Strengths of this trial include the methods used to minimize bias (blinded randomization assign-ments, a well-defined study protocol, complete follow-up, and intention-to-treat analyses). The re-cruitment of a large number of patients from 20 multidisciplinary ICUs where international stan-dards of care are followed suggests that our data can be generalized to other ICUs.

Limitations of the trial include the fact that our results were obtained for cisatracurium bes-ylate and may not apply to other neuromuscular blocking agents. Furthermore, we did not assess the use of a neuromuscular blocking agent late in the course of ARDS or use on the basis of plateau-pressure or transpulmonary-pressure measure-ments.20 Another limitation is the absence of data on conditions known to antagonize or potentiate neuromuscular blockade. However, any condition that increases the duration of neuromuscular blockade would have adversely affected the patients receiving the neuromuscular blocking agent, in particular by increasing the duration of mechani-cal ventilation.

The sample-size calculation was based on our two previous studies performed in four ICUs13,15 that used the same inclusion criteria as were used in the current trial and on the European epidemio-logic study ALIVE.4 However, the mortality in the placebo group in this study (40.7%) is lower than

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Table 1. Comparisons of the ACURASYS and ROSE Trials.*

Variable ACURASYS Trial ROSE Trial Commentary

No. of centers (location) 20 ICUs (Europe) 48 hospitals (United States) It is unlikely that different practices across the Atlantic would explain the different results of the two trials.

No. of patients (intervention group vs. control group)

340 (178 vs. 162) 1006 (501 vs. 505) Estimates for sample-size calculations were different.

Trial design for group assignment Double blind Unblinded Potential effect should be minimal.

ARDS definition American–European consensus Berlin criteria It is unlikely that this difference had a major effect on the char-acteristics of patients enrolled in the trials.

Criteria for moderate-to-severe ARDS PaO2:FIO2 <150 mm Hg with PEEP ≥5 cm of water

PaO2:FIO2 <150 mm Hg with PEEP ≥8 cm of water

ROSE allowed enrollment of patients with PaO2:FIO2 of 150–200 mm Hg after initial assessment but before randomization.

Median time from ARDS diagnosis to trial inclusion (IQR) — hr

16 (6–29) 8 (4–16) Earlier inclusion time in ROSE may have resulted in enrollment of some patients who might have died before they could have been enrolled in ACURASYS.

Intervention vs. control strategies Cisatracurium infusion plus deep sedation vs. deep sedation

Cisatracurium infusion plus deep sedation vs. light sedation

No routine neuromuscular blocking agents were allowed in the control groups.

Mechanical-ventilation approach Lung-protective ventilation with low PEEP

Lung-protective ventilation with high PEEP

In the first 7 days, PEEP levels were higher by about 2–3 cm of water in ROSE than in ACURASYS.

Monitoring of patient–ventilator dyssynchrony

Not reported Not reported Ideally, future studies should assess dyssynchronies.

ICU-acquired paresis and long-term outcomes

No difference between groups No difference between groups Patients in the control group in ROSE had higher mean levels of activity to day 6 than patients in the intervention group.

Serious adverse events Pneumothorax more frequent in the control group (11.7% vs. 4%)

Rates of overall barotrauma did not differ between groups

There were more acute cardiovascular events in the interven-tion group in ROSE than in the control group.

* Shown are comparisons between the ARDS et Curarisation Systematique (ACURASYS)2 and Reevaluation of Systemic Early Neuromuscular Blockade (ROSE)5 trials, which assessed the use of neuromuscular blocking agents in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). ICU denotes intensive care unit, IQR interquartile range, PaO2:FIO2 the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, and PEEP positive end-expiratory pressure.

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Asynchronies during mechanical ventilation are associated with mortality

Intensive Care Med 2015; 41:633–41

•⼈⼯呼吸器中の⾮同調の割合を調査•前向き観察研究• 50症例、7027hr、8,731,981サイクル• Asynchrony Index (AI)：10%以上で⾼頻度

study deals with a widely recognized clinical problem ofunknown magnitude.

The study also has potential limitations. This was apilot study with a limited power in 50 patients and wasnot designed to assess the effect of asynchrony on mor-tality. Moreover, the sample size was not calculated apriori because no data were available regarding the fre-quency of asynchronies during the entire MV period.Importantly, the study was confined to a single center andthe cohort consisted of a mixed population of medical andsurgical patients. As the incidence of asynchronies re-flects a center’s practice and expertise in ventilatorsettings, it might not be possible to extrapolate our resultsto other centers. Furthermore, unmeasured covariatessuch as patient factors (anxiety, dyspnea, ventilator drive,or neuromuscular status), different exposures to pain andsedative medication, and liberal selection of ventilatormode may have affected our results. Likewise, we cannotrule out the possibility that a specific MV mode, specificmachine type, or specific sedation strategy contributed topatient–ventilator asynchrony. Moreover, we did notstudy flow delivery problems during MV; whether flowmismatch is related to asynchronies remains unknown andwarrants future investigations. Furthermore, physiciansand nurses were aware of the nature of the study; how-ever, since the study was non-interventional and did notinterfere with usual patient care, we assume that patientsin this study received similar care to other patients in ourICU. Lastly, AI in VCV or PCV as compared to PSVcould be underestimated. By definition, no asynchronyoccurs during controlled ventilation in patients paralyzedor without spontaneous ventilation and asynchronies onlyappear after recovering spontaneous ventilation, even forreverse triggering. However, asynchronies can occurduring all periods of PSV and this could explain whyasynchronies were more frequent during PSV than duringVCV or PCV. We also excluded hours classified as CPAPor ‘‘other modes’’, in other words, hours in which patientsreceived ventilatory support in modes other than VCV,PCV, or PSV, hours in which the ventilatory mode wasmodified, and hours in which the system was unable todetermine the ventilatory mode. Therefore, we cannot

assess the impact of asynchronies that can develop in theroutine use of dual, proportional, and automated ventila-tion modes [38–40]. Since proportional modes couldpotentially lower the prevalence of asynchronies, disre-garding hours in those modes might overestimate theprevalence of asynchronies. However, it could also beargued that severe asynchrony might preclude correctventilatory mode detection.

The algorithm to detect short cycling and prolongedcycling has some limitations. In the context of alterationsof respiratory mechanics, the algorithm will identify shortcycling or prolonged cycling as an asynchrony only ac-cording to variations, half or double the inspiratory time(Ti) from the running mean of the previous 20 breaths. Inthe extreme case of alternating breaths of very short Titogether with breaths of prolonged Ti, such as in a one toone sequence, the algorithm will not detect short cyclingor prolonged cycling as asynchronies. This constitutes apotential major limitation of the algorithm’s performancein these circumstances.

The use of pneumatic signals provides information onasynchronies but precludes the understanding of the rela-tive differences in timing between neural output andventilatory activity, especially in patients with autoPEEP[41]. Although the measurement of esophageal pressure orelectrical activity of the diaphragm would have ensuredgreater accuracy in detecting all asynchronies [42], thenature of the present study precluded the application ofthese techniques to all patients. Therefore, we focused onthe asynchronies that can be easily identified and measuredby appropriate algorithms (aborted inspirations, short cy-cling, prolonged cycling, double-triggering, andautotriggering; see ESM) or mathematically validated al-gorithms that automatically detect IEE from airflowtracings in close agreement with experts and the EAdi [17].

Conclusions

In summary, we found that patient–ventilator asyn-chronies occur frequently, round the clock, and in the

Table 2 Relationship between AI and duration of MV, reintubation, tracheostomy, and ICU and hospital mortality by comparing patientsAI B 10 vs AI [ 10 %

AI B 10 % (n = 44) AI [ 10 % (n = 6) p value

Length of MV (days) 6 [5.0; 15.0] 16 [9.7; 20.0] 0.061Reintubation 9 (20 %) 0 (0 %) 0.57Tracheostomy 14 (32 %) 2 (33 %) 0.999ICU mortality 6 (14 %) 4 (67 %) 0.011*Hospital mortality 10 (23 %) 4 (67 %) 0.044*

Data are expressed as numbers and percentages or as medians and interquartile rangesMV mechanical ventilation, ICU intensive care unit, AI asynchrony index* Significant at p\ 0.05

639

•⾮同調は、⼈⼯呼吸器期間や死亡率を上昇させる。• Reverse trigger• Breath stacking → Over distension → VIDD, WOB上昇

• Pes/EAdiがないと認識するのは難しい• ARDSでどのくらい起こるかは不明（3-30%）• 深鎮静にしていても起こる

• ACURASYSのコントロール群は、深鎮静下でもbreath stacking・VILIが起こり、死亡率が悪化したと思われる。

Intensive Care Med 2019; 45:725–726Crit Care Med 2018; 46:e151–e157

Respir Care 2011;56(1):25-38

CHEST 2013; 143:927–938

この研究が意味するところ• Moderate〜severe ARDSにルーティンにNMBは使⽤しない• Breath stackingによりVILIを起こしそう、吸気努⼒が強く経肺圧が⾼い場合は、NMBを考慮する•⼈⼯呼吸器との⾮同調は、思っている以上にアウトカムに影響する•画⼀的なものではなく、個々の状況を鑑みARDSの状態に応じて、治療戦略を考える• NMBの安全⾯は⽰された

私⾒• P/F <150 ARDSにルーティンにNMBは使⽤しない•⾮同調をなくすように呼吸器を調整• NMBを考慮するとき• 吸気努⼒が強い場合

→ Pes/EAdiをモニタリングしながら• レスキューとして

→ Pplatを下げる、酸素化を改善する• 腹臥位療法を⾏う場合

→事故抜管などの管理⾯でも

NMB使⽤するとき•メリット• lung-protective (経肺圧を下げる)、同調性、VILI減少

•デメリット• 深鎮静、せん妄、VIDD、ICU-AW、⾓膜損傷・褥瘡、回路外れによるトラブル

•早期・短期間の使⽤にとどめる•（末梢神経刺激装置でのモニタリング）•（アミノステロイド系は使⽤しない）

Infusions of rocuronium and cisatracurium exert different effects on rat diaphragm function

Intensive Care Med 2007;33:872–879

• IMVで管理されているラット• CisatracuriumとRocuroniumの横隔膜に対する影響• 24時間持続投与（⽣⾷、Rocuro、Cisatra low, high）

876

Fig. 4 Correlation between MURF-1 mRNA levels in the diaphragmand diaphragm tetanic force in normal saline (closed circles), rocuro-nium (open circles), low-dose cisatracurium (closed squares) andhigh-dose cisatracurium (open squares) groups. The solid line anddotted lines represent the regression line and 95% confidence inter-vals, respectively

Expression of diaphragm MURF-1 and MAFbx/atrogin-1mRNA

Expression of MAFbx mRNA was not different betweenthe groups. MURF-1 mRNA expression in the diaphragmwas increased by 44% (p < 0.05 vs. normal saline and

Fig. 5 Ratio of calpain-cleaved to total αII-spectrin present in thediaphragm of animals in the normal saline, rocuronium, low-dosecisatracurium and high-dose cisatracurium groups. Bars as in Fig.3. Bands at 260 kDa represent intact αII-spectrin, and bands at 150and 145 kDa represent calpain-cleaved αII-spectrin. Values (meansand SE) are expressed as a percentage of the normal saline group.*p < 0.05 vs. all other groups

low-dose cisatracurium groups) in the rocuronium groupwhile it remained unchanged in both cisatracurium groups(Fig. 3). There was an inverse correlation between dia-phragmatic MURF-1 mRNA expression and diaphragmtetanic force (r = –0.71, p = 0.0005) (Fig. 4). Similar corre-lations were present for the other stimulation frequencies(–0.71 < r < –0.42, p < 0.05) (data not shown).

Calpain activity in the diaphragm

The ratio of calpain-cleaved αII-spectrin to total αII-spectrin, a reliable marker of calpain activity [20], washigher in the diaphragm of the rocuronium group thanin all other groups (p < 0.05) while unchanged in bothcisatracurium groups (Fig. 5). An inverse correlation wasfound between the diaphragmatic tetanic force and theratio of cleaved to total αII-spectrin in the diaphragm(r = –0.49, p < 0.05). Diaphragm levels of the endogenouscalpain inhibitor calpastatin were similar among the fourgroups (51379 ± 3491 AU, pooled values).

DiscussionOverview of the principal findings

This study shows for the first time a direct comparison ofthe effects of two NMBAs with different chemical corestructure on the diaphragm. The data show that continuousinfusion of an aminosteroidal neuromuscular blockingagent (i.e. rocuronium) during the course of 24 h of CMVin rats is more deleterious for diaphragm force than con-tinuous infusion of a similar effective dose of a benzyliso-quinoline agent (i.e. cisatracurium). Even when the dose ofcisatracurium is increased, the effect on diaphragm force isless detrimental than that of rocuronium at lower effectivedose. Moreover, rocuronium increased the expressionof MURF-1 mRNA and the calpain activity in the dia-phragm, while there were no significant changes observedin the diaphragm of the rats treated with cisatracurium.These data suggest that the decreased diaphragm forceafter rocuronium infusion is the consequence of a directeffect of rocuronium on the muscle caused by an increasedmyofilament cleavage and proteolysis. It appears from ourdata that cisatracurium infusion during MV in rats is lessharmful for the diaphragm than rocuronium infusion.

Experimental model and clinical relevance

The same animal model as in our previous study wasused [13]. Electromyographic measurements confirmedthat diaphragm activity was silenced in the differ-ent groups. The effective doses of rocuronium andcisatracurium used in this study are comparable with those

Saline Rocuro Lowcisatra

Highcisatra

ロクロニウムの投与で横隔膜障害の可能性を⽰唆

私⾒• CisatracuriumとRocuronium問題• Rocuronium (アミノステロイド系)はICU-AWの可能性があるにしても、⽣死を分ける状況では致し⽅ない

•腹臥位・Pes/EAdi・NMBを組み合わせた研究に期待