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Original research
Early neuromuscular blocking agents for adults with acute respiratory distress syndrome: a systematic review, meta-­ analysis and meta-­regression
Shuai Shao, Hanyujie Kang, Zhaohui Tong  ‍ ‍

To cite: Shao S, Kang H, Tong Z. Early neuromuscular blocking agents for adults with acute respiratory distress syndrome: a systematic review, meta-­analysis and meta-­regression. BMJ Open 2020;10:e037737. doi:10.1136/ bmjopen-2020-037737 ►► Prepublication history and additional materials for this paper is available online. To view these files, please visit the journal online (http://d​ x.​doi.​ org/​10.​1136/​bmjopen-​2020-​ 037737).
Received 14 February 2020 Revised 29 August 2020 Accepted 12 October 2020
© Author(s) (or their employer(s)) 2020. Re-­use permitted under CC BY-­NC. No commercial re-­use. See rights and permissions. Published by BMJ. Department of Respiratory and Critical Care Medicine, Beijing Chao-­Yang Hospital, Capital Medical University, Beijing, China
Correspondence to Dr Zhaohui Tong; ​[email protected]​sina.c​ om

ABSTRACT Objective  To determine whether neuromuscular blocking agents (NMBAs) can decrease the mortality of patients with acute respiratory distress syndrome (ARDS) and improve their clinical outcomes. Design  Systematic review, meta-­analysis and meta-­ regression. Data sources  PubMed, Embase, Cochrane Library, Web of Science and ​ClinicalTrials.​gov. Methods  Randomised controlled trials (RCTs) comparing the treatment effect of NMBAs with that of placebo (or traditional treatment) in patients with ARDS were carefully selected. The primary outcome was 90-­day mortality. The secondary outcomes were 21–28 days mortality, NMBA-­related complications (barotrauma, pneumothorax and intensive care unit (ICU)-­acquired muscle weakness), days free of ventilation and days not in the ICU by day 28, Medical Research Council score, Acute Physiology and Chronic Health Evaluation II score and arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) (at 48 hours and 72 hours). Random-­effects meta-­regression was used to explore models involving potential moderators. Trial sequential analysis was performed to estimate the cumulative effect on mortality across RCTs. Results  NMBAs were not associated with reduced 90-d­ ay mortality (risk ratio (RR) 0.85; 95% CI 0.66 to 1.09; p=0.20). However, they decreased the 21–28 days mortality (RR 0.71; 95% CI 0.53 to 0.96; p=0.02) and the rates of pneumothorax (RR 0.46; 95% CI 0.28 to 0.77; p=0.003) and barotrauma (RR 0.56; 95% CI 0.37 to 0.86; p=0.008). In addition, NMBAs increased PaO2/FiO2 at 48 hours (mean difference (MD) 18.91; 95% CI 4.29 to 33.53; p=0.01) and 72 hours (MD 12.27; 95% CI 4.65 to 19.89; p=0.002). Meta-r­egression revealed an association between sample size (p=0.042) and short-t­erm mortality. Publication year (p=0.050), sedation strategy (p=0.047) and sample size (p=0.046) were independently associated with PaO2/FiO2 at 48 hours. Conclusions  In summary, the results suggested that use of NMBAs might reduce 21–28 days mortality, NMBA-­ related complications and oxygenation. However, NMBAs did not reduce the 90-­day mortality of patients with ARDS, which contradicts a previous meta-­analysis. PROSPERO registration number  CRD42019139440.
INTRODUCTION Acute respiratory distress syndrome (ARDS) is a sudden and dangerous illness caused

Strengths and limitations of this study
►► This study is a comprehensive systematic review, including meta-­analysis and meta-r­egression, of the effectiveness of neuromuscular blocking agents for patients with acute respiratory distress syndrome; this study contains the most randomised controlled trials of any review on the topic.
►► We used trial sequential analysis to analyse short-­ term and long-­term mortality to increase the accuracy and stability of the results.
►► The quality of studies included in the systematic review was generally low, which made it difficult to draw clear conclusions.
by other sudden medical or surgical conditions, such as sepsis, injury, burn or severe pancreatitis.1 The symptoms of ARDS include hypoxia, which is difficult to correct, and patients always need life support with a ventilator in an intensive care unit (ICU).1–5 ARDS is typically associated with diseases and trauma conditions, which usually require multimodal treatment strategies that include both non-­pharmacological and pharmacological therapies.6 Although several treatments have been tested in patients with ARDS, this disease remains a highly lethal disease that affects almost three million people annually and accounts for 1/10 of all ICU admissions worldwide.7
In the 21st century, neuromuscular blocking agents (NMBAs) have played an important role as an adjuvant therapy in the ventilatory care of critically ill patients.8–10 Among all pharmacology-b­ased therapeutic strategies, only NMBAs are associated with a mortality reduction in patients with ARDS.6 NMBAs could cause skeletal muscle relaxation by blocking the transmission of nerve impulses at neuromuscular junctions, and non-d­epolarising NMBAs are widely used in the clinic because their metabolism is

Shao S, et al. BMJ Open 2020;10:e037737. doi:10.1136/bmjopen-2020-037737

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unrelated to renal or hepatic function.8 Several trials published over the past 15 years have demonstrated that NMBAs could achieve better clinical results in patients with ARDS than placebo, especially in terms of oxygenation and mortality.9 11–14 However, given the risk of neuromuscular dysfunction and other side effects, such as atelectasis and diaphragm paralysis, the use of NMBAs remains controversial and is usually not recommended in clinical guidelines for patients with ARDS.10 15–20 Recently, a new randomised controlled trial (RCT) published by Moss et al showed that NMBAs did not decrease the 90-d­ ay mortality among patients with ARDS compared with those who did not receive NMBAs.21 Subsequently, Chang et al performed a meta-a­nalysis to assess the efficacy of NMBAs and found that NMBAs could decrease the 90-d­ ay mortality, even after adding the results of the Rose trial.22 Although the outcomes of the study by Chang et al were similar to those in the previous meta-a­nalysis,23 their results may be limited. The 90-­day mortality data used in the study by Chang were pooled with 28-d­ ay mortality data, which might have affected the accuracy of the results. Considering the possible errors in Chang’s meta-­ analysis, it is necessary to conduct a new systematic review.
Furthermore, to guide drug therapy strategies for patients with ARDS, we performed this systematic review and meta-a­nalysis to identify whether NMBAs could improve the clinical outcomes of patients with ARDS.

Study selection Two reviewers (SS and HK) independently assessed each document for eligibility by screening the title, abstract and full text. All disagreements were resolved by discussion.
The inclusion criteria were as follows: (1) RCTs; (2) adult (aged over 18 years) patients who were diagnosed with ARDS by the consensus definition of the disease when the relevant study was published; (3) study groups that received NMBAs and control groups that received placebo without NMBAs and (4) studies that accurately and clearly provided any of the outcomes.
The exclusion criteria were as follows: (1) case reports, letters, systematic reviews, meta-­analyses, professional opinions or cohort studies; (2) studies lacking risk ratios (RRs), 95% CIs or continuous variable outcomes that could be converted to the mean and SD; (3) incorrect statistical methods that cannot be corrected and (4) incomplete data and unclear outcomes.
Data extraction and risk of bias assessment A double-­entry procedure was performed by two authors (SS and HK). In addition, the results of the data extraction were verified by a third author (ZT). The risk of bias of each study was assessed by two researchers (SS and HK). Any uncertainty was resolved through discussion with another person. We extracted the following data from the qualified studies: year of publication, country, name of

MATERIALS AND METHODS This meta-­ analysis was constructed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-­Analyses statement.
Patient and public involvement Patients and the public were not involved in planning the design and conducting, reporting or disseminating the results of our study.
Search strategy We performed a systematic literature search to identify relevant studies in the PubMed, Embase, Cochrane Library, Web of Science and ​ClinicalTrial.​gov databases from inception to 20 August 2020. Our search strategy combined concepts related to acute respiratory distress syndrome (ie, ‘shock lung’, ‘ARDSs, human’ and ‘respiratory distress syndrome’) and neuromuscular blocking agents (ie, ‘neuromuscular blockade’, ‘neuromuscular block’ and ‘neuromuscular blockers’) (see online supplemental table 1). We used the filters provided by the website of Cochrane Work to locate RCTs in PubMed and Embase. We applied no language restrictions, and we manually screened the search results to identify relevant RCTs and related pieces of literature. We studied the citations of each included article to find articles that met the inclusion criteria. Any uncertainty was resolved by discussion with the third researcher.
2

Figure 1  Screening process. NMBAs, neuromuscular blocking agents; RCTs, randomised controlled trials.
Shao S, et al. BMJ Open 2020;10:e037737. doi:10.1136/bmjopen-2020-037737

Shao S, et al. BMJ Open 2020;10:e037737. doi:10.1136/bmjopen-2020-037737

Table 1  Characteristics of included studies

Source Country Centres Eligibility

Criteria for enrolment

Methods

Strategy of ventilation

Main outcome

No of Group patients Patient intervention

Sedation strategy

Gainnier France (2004)9

Four ICUs

PaO2/FIO2 American-­ Prospective Volume-­assist/ The evolution of PaO2/FIO2 ratio NMBA 28

ratio of <150 European study

control (6–8 mL/ during the 120 hours; days free of

at a PEEP of consensus

kg ideal body

ventilation at day 28; days free of

≥5 cm H2O definition

weight)

ventilation at day 60; ICU death; mortality at day 28; mortality at Control 28 day 60; rates of barotrauma

Forel (2006)12

France

Three ICUs

PaO2/FIO2 American-­ Prospective Volume-­assist/ Inflammatory cytokines (tumour NMBA 18

ratio of <200 European study

control (4–8 mL/ necrosis factor, interleukin (IL)−1,

at a PEEP of ≥5 cm H2O

consensus definition

kg ideal body weight)

IL-6, and IL-8); PaO2/ FiO2 ratio; Total PEEP; Pplat; ICU death

Days free of ventilation at day 28;

rates of barotrauma

Control 18

Papazian France (2010)11

Twenty ICUs

PaO2/FIO2 ratio of <150
at a PEEP of
≥5 cm H2O

American-­ European consensus definition

Prospective study

Volume-­assist/ control (6–8 mL/ kg ideal body weight)

The 90- day mortality; ICU death; NMBA 177

Hospital death day-28 mortality;

Days not in ICU at day 28; Days

not in ICU at day 90; Days free

of ventilation at day 28; days free

of ventilation at day 90; rates of barotrauma

Control 162

Lyu (2014)13

China

One ICU

PaO2/FIO2 ratio of <150
at a PEEP of
≥5 cm H2O

The Berlin definition

Prospective study

Volume-­assist/ control (4–8 mL/ kg ideal body weight)

APACHE II score; SOFA; PaO2/ FiO2; ScvO2; Lactate and C reactive protein levels; 21 days
mortality

NMBA 48 Control 48

Yirao (2016)28

China

One ICU PaO2/FIO2 The Berlin Prospective Volume-­assist/ Gender, age, APACHE Ⅱ, PEEP, NMBA 24

ratio of <300 definition study

control (6 mL/kg FiO2, pH, PaO2, PaCO2, PaO2/

at a PEEP of

ideal body weight) FiO2, no of cases of pulmonary

≥5 cm H2O

atelectasis, no of cases of

ventilation in prone position; incidence of VAP, non-­ICU

Control 17

hospitalisation time and non

mechanical ventilation time

within 28 days, 28 days mortality,

90 days mortality

Guervilly France (2017)14

Two ICUs

PaO2/FIO2 The Berlin Prospective Volume-­assist/ Pplat; total PEEP; ICU mortality; NMBA 13

ratio of <150 definition study

control (6 mL/kg driving pressure; Inspiratory and

at a PEEP of ≥5 cm H2O

ideal body weight) expiratory PL and ∆PL; PaO2/ FiO2; days free of ventilation at day 28; days not in ICU at day 28 Control 11

Bolus of 50 mg cisatracurium, followed by a continuous infusion at an initial rate of 5 µg·k·min for 48 hours

Sedation (midazolam and sufentanil) was used to obtain a Ramsay score of 6

An infusion of saline at a rate of Sedation (midazolam and sufentanil)

4 mL/hour for 48 hours

was used to obtain a Ramsay score

of 6

A bolus of 0.2 mg/kg was followed by a continuous infusion at an initial rate of 5 µg·k·min for 48 hours

Sedation with midazolam and sufentanil was used to obtain a Ramsay score of 6

An infusion of placebo (saline) at a rate of 4 mL/hour for 48 hours

Sedation with midazolam and sufentanil was used to obtain a Ramsay score of 6

A 3 mL rapid intravenous infusion of 15 mg of cisatracurium, followed by a continuous infusion of 37.5 mg/ hour for 48 hours

Sedative medicine was used to obtain a Ramsay score of 6

A 3 mL rapid intravenous infusion of 15 mg of placebo, followed by a continuous infusion of 37.5 mg/hour for 48 hours

Sedative medicine was used to obtain a Ramsay score of 6

0.1 mg/kg vecuronium up to 0.05 mg/kg·hour for continuous intravenous infusion for 24–48 hours

Patients were given adequate sedation and analgesia with midazolam and sufentanil.

Give patients regular treatment

Patients were given adequate sedation and analgesia with midazolam and sufentanil.

Vecuronium 1 µg/kg·hour was given to maintain muscle relaxation and eliminate spontaneous respiration

Patients were given adequate sedation and analgesia with midazolam + morphine or midazolam + fentanyl combined

Give patients regular treatment

Midazolam + morphine or midazolam + fentanyl combined with sedation and analgesia were given. Ramsay Sedation score was given daily and controlled at 2–4 points

A3 mL rapid intravenous infusion of 15 mg cisatracurium, followed by a continuous infusion of 37.5 mg/hour

Sedation with midazolam and sufentanil was used to obtain a Ramsay score of 6

Give patients regular treatment

Sedation with midazolam and sufentanil was used to obtain a Ramsay score of 6

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Continued

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Table 1  Continued

Criteria for enrolment Methods

Strategy of ventilation

No of Group patients Patient intervention

Source Country Centres Eligibility

Main outcome

Sedation strategy

Moss (2019)21

USA

Forty-­ eight ICUs

PaO2/FIO2 – ratio of <150 at a PEEP of ≥8 cm H2O

Prospective study

Low tidal volume ventilation within 2 hours after randomisation and a high PEEP strategy for up to 5 days after randomis ation

In-­hospital death by day 90;

NMBA 501

In-­hospital death by day 28; days

free of ventilation at day 28; Days

not in ICU at day 28; Days not

A bolus of 15 mg of cisatracurium, followed by a continuous infusion of 37.5 mg/ hour for 48 hours Give patients regular treatment without routine NMBAs

in hospital at day 28; rates of barotrauma

Deep sedation evaluated by the Richmond Agitation-­Sedation Scale or the Riker Sedation Agitation Scale or the Ramsay Sedation Scale Light sedation evaluated by the Richmond Agitation-­Sedation Scale or the Riker Sedation Agitation Scale or the Ramsay Sedation Scale

Control 505

APACHE II, Acute Physiology and Chronic Health Evaluation; FiO2, fractional inspired oxygen; ICU, intensive care unit; NMBA, neuromuscular blocking agent; PaO2, arterial oxygen tension; PEEP, positive end-­expiratory pressure; SOFA, Sequential Organ Failure Assessment.

the first author, number of centres in each trial, criteria for enrolment, intervention description, outcomes, study methods, ventilation strategy, number of patients in each group, sedation strategy, outcome data, mean age, causes of ARDS, proportion of males and the Simplified Acute Physiology Score II score, Acute Physiology and Chronic Health Evaluation (APACHE) II score, arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2), tidal volume, plateau pressure (Pplat) and positive end-­ expiratory pressure (PEEP) at inclusion. If any data were inadequate, we emailed the corresponding authors. We used the Cochrane Collaboration risk of bias tool24 to examine the risk of bias of the included trials and judge the risk of bias as ‘low risk,’ ‘unclear’ or ‘high risk’ in each domain specified by the tool.
Outcomes The primary outcome was 90-d­ ay mortality. The secondary outcomes were 21–28 day mortality, days free of ventilation as of day 28, days not in the ICU as of day 28, NMBA-­ related complications (barotrauma, pneumothorax and ICU-­acquired muscle weakness), Medical Research Council (MRC) score, APACHE II score and PaO2/FiO2 at 48 hours and 72 hours.
Statistical synthesis and analysis The values of the categorical variables represent the RR and 95% CI. We generated summary estimates of the mean and SD of the continuous outcomes. The meta-­ analysis was performed using Mantel-H­ aenszel (M-­H) random-e­ffect models or, if the heterogeneity was not significant, fixed-e­ ffects models. A correction factor (1.0) was applied to zero-­event trials to enforce the effect of RR.25 We assessed the heterogeneity among the trials by using I2 testing (where a value >50% is regarded as indicative of substantial heterogeneity). If a primary or secondary outcome exhibited heterogeneity, we performed a subgroup analysis or sensitivity analysis to identify the source of heterogeneity. For the subgroup analysis, the following variables were selected before the study was performed: different inclusion criteria (PaO2/ FiO2<150 mm Hg, PaO2/FiO2<200 mm Hg, or PaO2/ FiO2<300 mm Hg); whether the patients were in the prone position; and whether lighter sedation was used in the control group than the NMBA group. All outcomes and subgroup analyses were planned a priori. We performed an interaction test in all subgroups to determine whether the difference between the subgroups was statistically significant. We judged the publication bias by creating a funnel plot and applying traditional statistical methods (Egger’s test) when more than five trials were included.26 The results were considered statistically significant at a p<0.05. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to judge the quality of evidence of the primary outcome and secondary outcomes. The statistical analyses were completed using Review Manager V.5.3, Stata V.15.1 and GRADE Profiler V.3.6.
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Table 2  Characteristics of patients at inclusion

Author/year

PaO2/FiO2(mm Hg, NMBAs/ placebo)

Tidal volume (mL/kg, Pplat (cm H2O,

NMBAs/placebo)

NMBAs/placebo)

Gainnier (2004)9 130±34/ 119±31

7.1±1.1/ 7.4±1.9

27.1±6.2/ 26.1±4.0

Forel (2006)12

−/−

6.5±0.7/ 7.0±0.7

27.5±4.4/ 24.8±5.7

PEEP (mm Hg, NMBAs/placebo) 11.1±2.8/ 10.9±2.4
13.2±2.7/ 11.1±2.7

Age, (yrs NMBAs/ placebo) 59.8±17.5/ 61.5±14.6
61±18/ 52±16

SAPSII
41.8±10.4/ 5.4±10.5 49±19/ 47±15

APACHEII −/− −/−

Papazian (2010)11 106±36/ 115±41

6.55±1.12/ 6.48±0.92 25.0±5.1/ 24.4±4.7 9.2±3.2/ 9.2±3.5

58±16/ 58±15

50±16/ 47±14 −/−

Lyu (2014)*13

140.95±26.97/ 144.33±24.09† −/−

−/−

−/−

58.4±8.2‡

−/−

18.20±3.59/

19.37±4.14†

 

77.68±11.21/ 80.61±12.82§ −/−

−/−

−/−

58.4±8.2‡

−/−

24.08±4.05/

23.20±5.04§

Yirao (2016)28

176±63/ 165±53

−/−

−/−

8±3/6±2

35±16/50±16

−/−

21±8/20±8

Guervilly (2017) 14 158(131,185)/ 150(121,187)

Moss (2019)21

98.7±27.9/ 99.5±27.9

6.2 (5.9, 6.8)/ 6.3 (6.0, 6.9)
6.3±0.9/ 6.3±0.9

23(19, 26)/ 21 (19, 25) 25.5±6.0/ 25.7±6.1

11 (10, 11.5)/ 10(9, 12) 12.6±3.6/ 12.5±3.6

72 (63; 79)/ 60 (52; 75) 56.6±14.7/ 55.1±15.9

47(37; 54)/ 48(42; 62)


−/−
103.9±30.1/ 104.9±30.1**

Prone position
Did not used in both group Did not used in both group
Used in both groups


Males (%) 75/71 78/67 – –





Used in both groups


87.5/76.5 69/91

Used in both groups

58.1/53.3

*Lyu et al divided patients into two group.
†Moderate group with PaO2/FiO2 ≤150 mm Hg. ‡In Lyu’s trial, the average age of all patients was given, but the average age of NMBAs group and placebo group were not provide.
§Severe group with PaO2/FiO2 ≤100 mm Hg) to evaluate the effect of NMBAs in patients with ARDS. Only the results of Guervilly were expressed as the median and interquartile range (25th and 75th percentiles).
**APACHE III was used in trial of Moss. Its scores range from 0 to 299, with higher scores indicating more severe illness.
‘–’, means unreported; APACHE II, Acute Physiology and Chronic Health Evaluation; ARDS, acute respiratory distress syndrome; NMBAs, neuromuscular blocking agents; PEEP, positive end-e­ xpiratory pressure; Pmean, mean pressure; Pplat,
plateau pressure; SAPS, Simplified Acute Physiology Score.

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Table 3  The risk of bias of eligible articles

Author/year

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Gainner (2004)9 U*

U*

Forel (2006)12

U*

U*

Papazian (2010)11 L

L

Lyu (2014)13

L

U*

Yirao (2016)28

L

L

Guervilly (2017)14 L

U*

Moss (2019)21

L

L

Performance bias
L H‡ L U* H‡ H‡ H‡

Detection bias
L† L† L L L† L L†

Attrition bias
L L L L L L L

Reporting bias
L L L L L L L

*The relevant information in the text was not mentioned and could not be judged. †Outcomes were less likely to be affected by single blind method (eg, mortality). ‡The article used the single blind method, that was, some participants (such as nurses) have broken the blindness. H, high risk; L, low risk; U, unclear.

Other bias
U* U* U* U* U* U* U*

Meta-regression A meta-­regression was performed using a random-e­ ffects model to explore the potential source of heterogeneity in our study. The following variables were selected before the meta-r­ egression was performed to explore the potential source of heterogeneity: publication year, race, baseline PaO2/FiO2, mean age, types of NMBAs, sedation strategy (whether lighter sedation was used in the control group than the NMBA group), whether the prone position was used, article sample size, proportion of ARDS cases arising from intrapulmonary causes, baseline PEEP, baseline Pplat and baseline tidal volume.
Trial sequential analysis Trial sequential analysis (TSA) uses a combination of techniques to eliminate early false positive findings due to imprecise outcomes and repeated trials in a meta-­ analysis.27 We applied the analysis to the 21–28 days mortality and 90-­day mortality data. In this part, a

Z-c­urve was constructed to represent mortality, and a conventional threshold of z=1.96 was used to identify whether the result was meaningful. We chose the O’Brien-F­leming alpha to construct adjusted trial sequential monitoring boundaries. The setting of the analysis was estimated using a two sided of 0.05 and a β of 0.20 (power:80%) to limit the type I and type II errors. The incidence rates of 35.2% and 41.8% in the control arm were selected because these rates were compatible with most large-s­cale RCTs included in this study. The estimated information size obtained by the TSA refers to the number of cases needed in a meta-­ analysis to obtain statistically significant differences, that is, the sample size necessary for the meta-­analysis. TSA provides a termination standard for clinical trials by estimating the estimated information size, that is, when the cumulative number of cases in the meta-­ analysis reaches the expected amount of information

Figure 2  (A) Forest plot showing the 90-­day mortality of acute respiratory distress syndrome patients. (B) Forest plot showing the 21–28 days mortality of acute respiratory distress syndrome patients. M-­H, Mantel-H­ aenszel; NMBAs, neuromuscular blocking agents.

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Table 4  The outcomes of the study Outcomes or subgroup analysis

Studies Study reference no Patients RR/MD (95% CI)

I2

P value

Primary outcomes

 90  days mortality

5

(9, 11, 14, 21, 28) 1466

0.85 (0.66 to 1.09)

Secondary outcomes

 21–28  days mortality

6

(9, 11–13, 21, 28)

1574

0.71 (0.53 to 0.96)

 Days free of ventilation at day 28

5

(9, 11, 12, 14, 21) 1461

0.54 (−0.47 to 1.56)

 Barotrauma*

4

(9, 11, 12, 21)

1439

0.56 (0.37 to 0.86)

 Pneumothorax†

2

(11–21)

1345

0.46 (0.28 to 0.77)

 ICU acquired muscle weakness

3

(11, 12, 21)

691

1.19 (0.99 to 1.44)

 Days not in the ICU at day 28

3

(11, 14, 21)

1369

0.16 (−1.00 to 1.31)

 APACHE II score

2

(13–28)

137

−2.07 (−3.17 to -0.97)

 MRC score

2

(11–21)

1345

−2.24 (−6.24 to 1.76)

 PaO2/FiO2 at 48 hours

5

(9, 12–14, 21)

 PaO2/FiO2 at 72 hours

4

(9, 11–12, 21)

Subgroup analysis of 21 to 28 day mortality (PaO2/FiO2)

 ARDS with PaO2/FiO2 <200 mm Hg 1 (12)

 ARDS with PaO2/FiO2 <300 mm Hg 1 (28)

 ARDS with PaO2/FiO2 <150 mm Hg 4

(9, 11, 13, 21)

Subgroup analysis of 21–28 days mortality (prone position)

1218 1437
36 41 1497

18.91 (4.29 to 33.53) 12.27 (4.65 to 19.89)
0.50 (0.21 to 1.17) 0.35 (0.03 to 3.60) 0.75 (0.54 to 1.02)

 Did not used prone position in both 2 group

(9–12)

92

0.56 (0.35,0.90)

 Used prone position in both group 4

(11, 13, 21, 28)

1386

0.86 (0.64,1.16)

Subgroup analysis of 21–28 days mortality (whether used lighter sedation in control group)

 Used lighter sedation in control group 2

(21–28)

1047

0.98 (0.84 to 1.16)

 Used deep sedation in control group 4

(9, 11–13)

1574

0.63 (0.49 to 0.82)

Sensitive analysis

 90  days mortality†

4

(9, 11, 14, 28)

460

0.75 (0.56 to 1.00)

 21–28  days mortality‡

5

(9, 11–13, 28)

568

0.63 (0.48 to 0.81)

 PaO2/FiO2 at 48 hours‡

4

(9, 12–14)

1182

13.08 (0.96 to 25.20)

46%
51% 15%
0% 0% 0% 17% 35% 84% 59% 37%
– – 62%
0%
45%
0% 0%
13% 0%
46%

0.2
0.02 0.3 0.008 0.003 0.07 0.79 2E-04 0.27 0.01 0.002
0.58§
0.13§
0.005§
0.05 4E-04 0.03

Barotrauma is defined as any new pneumothorax, pulmonary mediastinum, subcutaneous emphysema or pulmonary bulge larger than 2 cm in diameter. *Pneumothorax refers to the entry of gas into the pleural cavity, causing a state of pneumothorax, called pneumothorax. †Sensitive analysis of primary outcome. ‡Sensitive analysis of secondary outcomes. § Values of test of interaction between subgroups. APACHE II, Acute Physiology and Chronic Health Evaluation II; FiO2, fractional inspired oxygen; ICU, intensive care unit; MD, mean difference; MRC score, The Medical Research Council score; PaO2, arterial oxygen tension; RR, risk ratio.

and similar clinical trials can be terminated to avoid wasting scientific research and medical resources. The software TSA 0.9.5.10 beta was used for the entire analysis.
RESULTS After systematically searching five electronic databases, we obtained 1087 articles according to the search strategy as follows: PubMed (n=364), Embase (n=308), Cochrane library (n=101), Web of Science (n=312) and C​ linicalTrial.g​ ov (n=2). Among these articles, 211 studies were excluded because they were duplicates. Eight hundred
Shao S, et al. BMJ Open 2020;10:e037737. doi:10.1136/bmjopen-2020-037737

and forty-s­even studies were excluded because they did not meet our inclusion criteria after we reviewed their titles and abstracts. The remaining 29 studies were considered relevant, and we carefully screened the full articles. Nine studies did not focus on patients with ARDS, and eight reviews, four comments and one paediatric RCT were discarded. Ultimately, 7 RCTs involving a total of 1598 patients were included in this systematic review and meta-a­ nalysis. The screening process is shown in figure 1.
Study characteristics The number of patients in a single trial ranged from 24 to 1006. In total, four trials were conducted by the same
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Figure 3  Forest plot showing the days free of ventilation at day 28 of acute respiratory distress syndrome patients. NMBAs, neuromuscular blocking agents.

research group in France.9 11 12 14 Another two trials were conducted in China,13 28 and the last trial was conducted in the USA.21 Five eligible studies included patients with
moderate to severe ARDS whose PaO2/FiO2 was less than 150 mm Hg.9 11 13 14 21 However, in the studies by Yirao et al28 and Forel et al12 the PaO2/FiO2 values were <300 mm Hg and <200 mm Hg, respectively. In the trial by Moss et al,21 the baseline PEEP was greater than 8 cmH2O, but in the remaining trials, the PEEP threshold was 5 cmH2O.9 11–14 28 The mean PEEP value of the patients at inclusion in the Rose trial21 was 12.6 cmH2O, but in Gainner’s trial,9 the mean was 11.0 cmH2O. The prone position was applied in three eligible studies,11 21 28 and
the proportion of patients who were treated in the prone
position did not statistically significantly differ among
these three studies. In addition, on average, the included patients were younger in the study by Yirao et al28 (mean age=42.5 years) and older in the study by Guerville et al14
(mean age=66 years) than those in the other trials. The
characteristics of the studies are presented in table 1, and

the details of the characteristics of the patients at inclusion are shown in table 2.
Risk of bias Regarding the bias of the individual trials, three trials were judged to have an unclear risk of bias.9 11 13 The remaining trials were assessed as having a high risk of bias because of deficits in the blinding methods12 14 21 28 (table 3). Further details are shown in online supplemental figures 1 and 2.
Primary outcome Ninety-day mortality Five trials involving a total of 1466 patients examined the 90-­day mortality.9 11 14 21 28 Overall, these trials demonstrated that NMBAs did not decrease the 90-­day mortality (RR 0.85; 95% CI 0.66 to 1.09; p=0.20). The statistical heterogeneity was acceptable (I²=46%) (figure 2A) (table 4). Due to the importance of this outcome, we

Figure 4  (A) Forest plot showing the occurrence of ICU acquire muscle weakness of acute respiratory distress syndrome patients. (B) Forest plot showing the rate of pneumothorax of acute respiratory distress syndrome patients. (C) Forest plot showing the rate of barotrauma of acute respiratory distress syndrome patients. ICU, intensive care unit; M-H­ , Mantel-­Haenszel; NMBAs, neuromuscular blocking agents.

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Figure 5  (A) APACHE score. (B) MRC score. APACHE, Acute Physiology and Chronic Health Evaluation; MRC, Medical Research Council; NMBAs, neuromuscular blocking agents.

analysed the possible sources of heterogeneity by a meta-­regression.
Secondary outcomes Twenty-one-day to 28-day mortality Six RCTs published over the past 15 years were eligible for inclusion in this analysis.9 11–13 21 28 Further information is provided in figure 2B. NMBAs were associated with a reduced 21–28 days mortality in the M-H­ random-­effects model (RR 0.71; 95% CI 0.53 to 0.96; p=0.02; I²=51%) (table 4).
Days free of ventilation at day 28 Five trials9 11 12 14 21 involving a total of 737 participants in the interventional groups (table 4) and 724 patients in the control groups reported the number of days free of ventilation at day 28. Our meta-a­nalysis indicated that there was no significant intergroup difference in the number of days free of ventilation at day 28 (mean difference (MD) 0.54; 95% CI −0.47 to –1.56; p=0.30), and there was no heterogeneity among the five trials (I²=15%). All details are shown in figure 3.

NMBA-related complications (barotrauma, pneumothorax and ICU-
acquired muscle weakness)
Four studies involving 1439 patients reported barotrauma.9 11 12 21 Two studies reported the rate of pneumothorax in a total of 1345 patients.11 21 In addition, three
eligible studies provided the rate of ICU-a­ cquired muscle weakness in a total of 691 patients.11 12 21 A fixed-e­ ffects
model was applied to NMBA-r­elated complications.
For the zero-­event trials, we added 1.0 as a correction factor.9 12 25 Compared with the non-­NMBA treatment,
NMBAs did not increase the occurrence of ICU-a­ cquired
muscle weakness (RR 1.19; 95% CI 0.99 to 1.44; I²=0%; p=0.07)11 12 28 (figure 4A) (table 4). Using NMBAs in
patients with ARDS may improve survival outcomes by reducing the rates of pneumothorax11 21 (RR 0.46; 95% CI 0.28 to 0.77; p=0.003; I²=0%) and barotrauma9 11 12 21 (RR
0.56; 95% CI 0.37 to 0.86; p=0.008; I²=0%) (figure 4B,C)
(table 4).

Figure 6  (A) Forest plot showing the PaO2/FiO2 at 48 hours. (B) Forest plot showing the PaO2/FiO2 at 72 hours. FiO2, fractional inspired oxygen; NMBAs, neuromuscular blocking agents; PaO2, arterial oxygen tension.

Shao S, et al. BMJ Open 2020;10:e037737. doi:10.1136/bmjopen-2020-037737

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Figure 7  Meta-­regression of 21–28 days mortality (sample size).
Days not in the ICU at day 28 Three studies involving 1369 patients reported the days not in the ICU at day 28.11 14 21 The treatment regimens involving NMBAs were not helpful in increasing the days not spent in the ICU as of day 28 (MD 0.16; 95% CI −1.00 to –1.31; p=0.79), and there was no heterogeneity among the trials (I²=17%) (see online supplemental figure 3) (table 4). APACHE II score and MRC score Two studies involving a total of 137 patients reported the APACHE II scores.13 28 These scores significantly differed between the two groups, and the level of heterogeneity was acceptable (MD −2.07; 95% CI −3.17 to −0.97; p=0.0002; I²=35%) (figure 5A). Two studies included 1345 patients reported the MRC score.11 21 We found no statistically significant difference between the two groups in terms of the MRC scores (MD −2.24; 95% CI −6.24 to 1.76; p=0.27; I²=84%) (figure 5B).

PaO2/FiO2 at 48 hrs and 72 hrs A random-­effects model was used because significant heterogeneity was present. There was a significant effect of NMBAs on PaO2/FiO2 at 48 hrs9 12–14 21 (MD 18.91; 95% CI 4.29 to 33.53; p=0.01; I2=59%) (figure 6A). After we excluded Forel’s trial, the heterogeneity of PaO2/ FiO2 at 48 hours was acceptable12 (MD 13.08, CI 0.96 to 25.20; p=0.03; I2=46%). Four studies involving a total of 1437 patients were eligible for the PaO2/FiO2 at 72 hours analysis.9 11 12 21 There was a significant increase in PaO2/FiO2 at 72 hours with mild heterogeneity (MD 12.27; 95% CI 4.65 to 19.89; p=0.002; I2=37%) (figure 6B) (table 4).
Meta-regression In the meta-r­egression, we did not find the potential source of heterogeneity in the 90-­day mortality data. Regarding the 21–28 days mortality, the meta-r­egression analysis showed that the difference in the sample size was associated with heterogeneity (p=0.042) (figure 7). Furthermore, the following variables were found to be independently associated with PaO2/FiO2 at 48 hours: publication year (p=0.050), article sample size (p=0.046) and sedation strategy (p=0.047) (see online supplemental figure 4) (table 5).
Subgroup analysis and sensitivity analysis We performed a sensitivity analysis by sequentially omitting each trial to identify the possible main sources of heterogeneity in the 90 day mortality and 21–28 day mortality data. We found that when we omitted the Rose trial,21 the heterogeneity of the 90-d­ ay mortality decreased from 46% to 13% (RR 0.75; 95% CI 0.56 to 1.00; p=0.05; I²=13%) (see online supplemental figure 5). Similarly, the heterogeneity of the 21–28 day mortality disappeared when the Rose trial21 was excluded (RR 0.63; 95% CI 0.48 to 0.81; p=0.0004) (see online supplemental figure 6). There is no significant change in the global RR of 90-d­ ay mortality or 21–28 days mortality compared with before.

Table 5  Meta-­regression

Outcomes
90 days mortality
21*–28 days mortality
PaO2/FiO2 at 48 hours

Year 0.118 0.061 0.050†

Race 0.357 0.299 0.97

Baseline PaO2/ FiO2 0.273
0.379
0.952

Mean age 0.434
0.744
0.396

Type of NMBA 0.357
0.299
0.97

Article Pulmonary sample disease size

0.15

0.15

0.163

0.042†

0.976

0.046†

Baseline PEEP 0.619
0.681
0.956

Baseline Baseline tidal pplat volume

0.21

0.405

0.13

0.161

0.088 0.803

Whether lighter sedation was applied 0.208

0.047†

Whether prone position was applied 0.452
0.089
0.21

*Since we did a subgroup analysis of the results and the p value was meaningful, we did not do the corresponding meta-r­egression.
†The results were statistically significant.
FiO2, fractional inspired oxygen; NMBAs, neuromuscular blocking agents; PaO2, arterial oxygen tension; PEEP, positive end-­expiratory pressure.

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