Neuromuscular blocking agents for patients with acute respiratory distress syndrome

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

We will assess the effectiveness and safety of using neuromuscular blocking agents within 48 hours of initiation of mechanical ventilation for ARDS patients.

Background

Description of the condition

Acute respiratory distress syndrome (ARDS) is characterized by progressive hypoxaemic and respiratory failure. ARDS is defined by a ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) of less than 300 mm Hg. ARDS is divided into three mutually exclusive categories based on degree of hypoxaemia: mild (200 mm Hg < PaO2/FiO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FiO2 ≤ 200 mm Hg), and severe (PaO2/FiO2 ≤ 100 mm Hg) (ARDS definition taskforce 2012). Pathologically, ARDS is characterized by interstitial and alveolar oedema, caused by damage to the endothelial cells of the pulmonary capillaries and the alveolar epithelial cells. This leads to small lung volume, poor lung compliance and serious imbalance of the ventilation/blood flow ratio. Chest radiograph shows bilateral non-uniform infiltrates. The following aetiological factors are associated with ARDS: sepsis, trauma, multiple blood transfusions, pancreatitis, inhalation injury and certain types of drug toxicity (Dushianthan 2011). Both medical and surgical patients can develop ARDS (Ware 2000). The incidence is 64 cases per 100,000 person-years, and the mortality rate is 40% to 50% (Malhotra 2007). Hypoxaemia is a core feature of ARDS. Because of the respiratory and systemic insult and the challenge of managing hypoxaemia, a variety of mechanical ventilation strategies have been considered (Boyadjiev 2008). These strategies include conventional mechanical ventilation, lung-protective ventilation and high-frequency ventilation. High-frequency ventilation is generically defined as any application of mechanical ventilation with a respiratory rate that exceeds 100 breaths/min (Henry 2007). Lung-protective mechanical ventilation with low tidal volume (6 mL/kg), moderate positive end-expiratory pressure (PEEP) and a plateau pressure limitation of < 30 cm H2O can improve survival and reduce circulating inflammatory cytokines (Dushianthan 2011). Neuromuscular blocking agents (NMBAs) have frequently been used to facilitate mechanical ventilation and improve patient-ventilatory synchrony when sedation alone is inadequate. However, one serious associated adverse effect is prolonged paralysis following discontinuity of NMBAs (Segredo 1992). Therefore, routine use of NMBA in patients with ARDS, although a frequent practise, remains controversial.

Description of the intervention

Non-depolarizing NMBAs are classic competitive inhibitors at the postsynaptic nicotinic acetylcholine receptor (nAChR) in the neuromuscular junction (Jonsson 2006; Jonsson 2009). Clinically used nondepolarizing NMBAs include atracurium, cis-atracurium, mivacurium, pancuronium, rocuronium, vecuronium and d-tubocurarine (Jonsson 2009).

How the intervention might work

Mechanical ventilation plays a role in correcting hypoxaemia (Boyadjiev 2008), and mortality can be significantly reduced at day 28 with lung-protective mechanical ventilation (Petrucci 2013). The objectives of sedation are to facilitate mechanical ventilation, to improve gas exchange by controlling agitation and to reduce mechanical ventilation–associated injuries (Boyadjiev 2008). Sedation levels vary according to the medical condition of individual patients and treatment needs. The purpose of using an NMBAs is to promote patient-ventilator synchrony while improving oxygenation (Sessler 2004) for ARDS patients who are sedated by eliminating spontaneous breathing. An improvement in chest wall compliance and reduced oxygen consumption as a result of NMBAs may account for improvement in oxygenation. Lower concentrations of pulmonary and systemic proinflammatory cytokines and a reduction in pulmonary inflammation associated with ARDS may be seen in patients treated with NMBAs (Forel 2006). Early usage of a neuromuscular blocking agent has been shown to improve adjusted 90-day survival in patients with severe ARDS, to increase time spent off mechanical ventilation and to reduce the length of intensive care unit (ICU) stay without increasing muscle weakness (Papazian 2010). However, weakness acquired in the ICU is seen in a large proportion of critically ill patients (Deem 2006). Concerns have been raised about the risks of prolonged weakness due to NMBA-induced myopathy, especially with concomitant use of corticosteroids (Forel 2006; Latronico 2005). ICU-acquired paresis (ICUAP) was defined as symmetrical limb muscle weakness in at least two muscle groups at ICU discharge with no other explanation (Brunello 2010). Muscle strength was evaluated using the Medical Research Council (MRC) score (Papazian 2010).

Why it is important to do this review

ARDS is associated with a relatively high mortality. Mechanical ventilation is an essential component of therapy for ARDS patients. When sedation alone is inadequate for facilitating ventilation, neuromuscular blockers may be beneficial because they have the potential to promote patient-ventilator synchrony, improve gas exchange and decrease lung and systemic inflammation. However, questions remain as to whether there is risk of developing ICU-acquired paresis and whether survival is increased. At present, evidence is insufficient for clinical decision making. The aim of this systematic review is to address this lack of evidence.

Objectives

We will assess the effectiveness and safety of using neuromuscular blocking agents within 48 hours of initiation of mechanical ventilation for ARDS patients.

Methods

Criteria for considering studies for this review

Types of studies

We will include all randomized controlled trials (RCTs) that assess the effectiveness and safety of neuromuscular blocking agents in participants with ARDS.

We will include quasi-randomized trials. Their quality will be assessed subsequently, and they will be subject to sensitivity analysis.

We will exclude cohort studies and cross-over design studies.

Types of participants

We will include all ARDS patients (PaO2/FiO2 ratio ≤ 300 mm Hg at a PEEP ≥ 5 cm H2O) who are receiving appropriate sedation (the sedation level varies according to the medical condition of individual patients) and mechanical ventilation.

We will exclude patients who have clinical evidence of left atrial hypertension. We will also exclude patients with severe chronic respiratory disease requiring long-term oxygen therapy or mechanical ventilation.

Types of interventions

We will consider patients who were given conventional therapy plus non-depolarizing NMBA as constituting the intervention group, and conventional therapy alone will be provided to the control group.

Alternatively, conventional therapy plus a non-depolarizing NMBA will be given to the intervention group, and conventional therapy plus placebo will be provided to the control group.

Conventional therapy is defined as treatment of the underlying cause when possible, as well as mechanical ventilation, strict control of liquid input, multi-organ support, appropriate antimicrobial therapy and early enteral nutrition.

Before using neuromuscular blocking agents, all included participants should have received sedation and mechanical ventilation.

Types of outcome measures

Primary outcomes
  • Survival rate at 28 days and 90 days: defined as the proportions of participants who survived within 28 days and 90 days after study enrolment.

  • Rate of ICUAP: the proportions of participants with MRC score <48 on day 28 and on day 90.

Secondary outcomes
  • PaO2/FiO2 ratio: PaO2 and FiO2 as measured by means of arterial blood gas estimation before randomization and on day 28.

  • Time off the ventilator in ICU: Off the ventilator is defined as the number of days of spontaneous breathing lasting at least 48 consecutive hours after weaning from mechanical ventilation between day one and day 28 and between day one and day 90.

  • Number of days outside the ICU: refers to the numbers of days outside the ICU between day one and day 28 and between day one and day 90.

  • Relative inflammatory factors: refers to concentrations of tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and IL-8 in bronchoalveolar lavage fluid and blood samples before randomization and on day 28.

  • Number of days without organ failure: Organ failure refers to circulatory failure, hepatic failure, renal failure or coagulation failure and will be calculated by subtracting the number of days with organ failure from 28 days or from the number of days until death, if death occurred before day 28.

  • Incidence of barotrauma: defined as any new pneumothorax, pneumomediastinum, subcutaneous emphysema or pneumatocele larger than 2 cm in diameter on day 28 and on day 90.

Search methods for identification of studies

Electronic searches

We will search the following databases: the latest issue of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, from 1978 to date) and EMBASE (Ovid SP, from 1975 to date). We will apply no language or publication restrictions.

We will use the sensitivity maximizing search strategies described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to search for RCTs in MEDLINE and EMBASE. We will use free-term and associated exploded MeSH terms in the process of the search strategy. According to the search results, we will add any new free-text terms or MeSH terms to the search strategy, and we will report the revised search strategy in the final review.

The search strategies for CENTRAL, MEDLINE and EMBASE are provided respectively in Appendix 1, Appendix 2 and Appendix 3.

Searching other resources

We will screen the reference lists of all eligible trials and reviews. We will screen Science Citation index (SCI) and related conference papers.

We will search the following databases for ongoing trials: http://www.controlled-trials.com and http://clinicaltrials.gov.

We will use free-text terms in all databases, but when thesauri are a component of a database, we will use subject headings. We will not search manually. We will contact corresponding authors in the field to identify unpublished research and trials that are still under way.

Data collection and analysis

Selection of studies

We will use the Reference Manager software to manage studies of the searches above. We will exclude any obvious duplicate publication of the study. Two review authors (ZG and LJY) will independently select studies and will not be blinded to any details of studies. We will independently screen all titles and abstracts for eligibility (Appendix 4 and Appendix 5). We will exclude obviously irrelevant studies and will give the reasons for their exclusion. We (ZG and LJY) will read the full text of relevant studies to decide whether these studies should be included in the review. We will resolve disagreements initially by discussion. If the discussion does not resolve the differences, we will ask a third review author (QH) to arbitrate on study inclusion. If information in the study is insufficient, we will contact the first author of the relevant study (ZG).

We will record all eligible trials using a trials form (Appendix 6).

Data extraction and management

Two review authors (ZG and LJY) will independently extract and collect data from each trial and will record information on the data extraction form (Appendix 7). We will resolve any disagreements on data extraction by discussion. If, after discussion, we are unable to reach a consensus, we will consult a third review author (QH). If further information is required, we (ZG) will contact the first author of the relevant trial.

Assessment of risk of bias in included studies

Two review authors (ZG and LJY) will independently carry out assessment of methodological quality of all eligible trials. We will resolve disagreements by discussion; if, after discussion, we still cannot reach a consensus, a third review author (QH) will arbitrate. We will reference the risk of bias tool described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to perform risk of bias assessment of all eligible trials. The form we will use is provided in Appendix 8. We will assess each trial according to the following domains.

  • Random sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of outcome assessment.

  • Incomplete outcome data.

  • Selective reporting.

  • Other bias.

We will consider a trial as having a low risk of bias if all domains are assessed as adequate. We will consider a trial as having a high risk of bias if one or more domains are assessed as inadequate or unclear.

We will construct a risk of bias graph and a risk of bias summary figure using RevMan 5.1.

Measures of treatment effect

For dichotomous data, we will use risk ratios (RRs) with 95% confidence intervals (CIs). For continuous data, we will use the mean difference (MD) if outcome data were reported on the same scale or the standardized mean difference (SMD) for different scales with 95% CIs.

Unit of analysis issues

The individual will be regarded as the unit of analysis.

Dealing with missing data

We will contact the original investigators of included trials to request missing data (ZG). We will conduct an intention-to-treat (ITT) analysis of relevant trials, if necessary. We will calculate missing standard deviations (SDs) from the standard errors (SEs) or confidence intervals, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If SDs cannot be calculated, we will impute these by using the mean of the reported SDs from the other trials.

Assessment of heterogeneity

Variability in participants, interventions and outcomes studied may be described as clinical heterogeneity, whereas variability in study design and risk of bias may be described as methodological heterogeneity. Meta-analysis should be considered only when a group of studies is sufficiently homogeneous in terms of participants, interventions and outcomes.

We will assess clinical heterogeneity according to the detailed clinical characteristics, and we will assess the risk of bias as methodological heterogeneity.

We will use the Chi2 test of heterogeneity and will consider P ≤ 0.10 as evidence of significant heterogeneity. We will also use the I2 statistic to assess heterogeneity. We will consider heterogeneity important when I2 is greater than 50% (Higgins 2011).

Assessment of reporting biases

If at least 10 trials are included in the meta-analysis, we will investigate reporting biases. We will assess publication bias by using a funnel plot, and we will test for funnel plot asymmetry (small-study effects) by using the statistical methods described in Rucker 2008.

Data synthesis

For dichotomous outcomes, the Mantel-Haenszel statistical method will be used, and data will be pooled using common RRs and 95% CIs. For continuous outcomes, the inverse variance statistical method will be used. The MD (for variables using the same unit of measure) and the 95% CI will be calculated. All data will be combined by using a fixed-effect model when the I2 value is less than 50%; otherwise, a random-effects model will be used. We will perform all analyses using RevMan 5.1 software.

Subgroup analysis and investigation of heterogeneity

We will perform subgroup analyses for subgroups of participants and interventions.

Subgroups of participants
Different PaO2/FiO2 ratio at the onset of ARDS.

Subgroups of interventions

Different types of non-depolarizing NMBAs.

Different types of mechanical ventilation strategies.

Sensitivity analysis

We will compare the two models of data synthesis: random-effects model and fixed-effect model. We will carry out sensitivity analysis by pooling data after exclusion of the trials with no mention of unclear allocation concealment and blinding of participants, personnel and outcome assessment.

Summary of findings

We will use the principles of the GRADE system (Guyatt 2008) in our review to assess the quality of the body of evidence associated with the specific outcomes (survival rate, ICU-acquired paresis, PaO2/FiO2 ratio, ventilator-free days, days outside the ICU. relative inflammatory factors, days without organ failure and barotrauma) and to construct a summary of findings (SoF) table. The GRADE approach appraises the quality of a body of evidence according to the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. Assessment of the quality of a body of evidence considers within-study risk of bias (methodological quality), directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias.

Acknowledgements

We thank Jane Cracknell (Managing Editor, Cochrane Anaesthesia Review Group (CARG)) and Karen Hovhannisyan (Trial Search Co-ordinator, CARG) for their assistance in the preparation of this protocol. We would also like to thank Mathew Zacharias and Rodrigo Cavallazzi (content editors), Marialena Trivella (statistical editor) and Ahilanandan Dushianthan and Tamas Szakmany (peer reviewers) for their help and editorial advice during the preparation of this protocol for the systematic review.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Respiratory Distress Syndrome, Adult explode all trees
#2 MeSH descriptor Hyaline Membrane Disease explode all trees
#3 MeSH descriptor Acute Chest Syndrome explode all trees
#4 MeSH descriptor Respiration Disorders explode all trees
#5 (respiratory near (distress syndrome)) or ARDS or (acute near (lung or chest or respiratory)) or (lung near (shock or failure or injury)) or (pulmonary near (capillary leak*))
#6 (#1 OR #2 OR #3 OR #4 OR #5)
#7 MeSH descriptor Neuromuscular Blocking Agents explode all trees
#8 MeSH descriptor Muscle Relaxants, Central explode all trees
#9 neuromuscular near block*
#10 (#7 OR #8 OR #9)
#11 (#6 AND #10)

Appendix 2. MEDLINE (Ovid SP) search strategy

1. exp Respiratory Distress Syndrome,Adult/ or exp Hyaline Membrane Disease/ or exp Acute Lung Injury/ or exp Acute Chest Syndrome/ or exp Respiration Disorders/ or (respiratory adj3 distress syndrome).mp. or ARDS.mp. or (acute adj3 (lung or chest or respiratory)).mp. or (lung adj3 (shock or failure or injury)).mp. or (pulmonary adj3 capillary leak*).mp.
2. exp Neuromuscular blocking agents/ or exp Muscle Relaxants, Central/ or (neuromuscular adj3 block*).af.
3. 1 and 2
4. ((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.) not (animals not (humans and animals)).sh.
5 3 and 4

Appendix 3. EMBASE (Ovid SP) search strategy

1. exp adult respiratory distress syndrome/ or exp hyaline membrane disease/ or exp acute lung injury/ or exp acute chest syndrome/ or exp breathing disorder/ or exp shock lung/ or (respiratory adj3 distress syndrome).mp. or ARDS.mp. or (acute adj3 (lung or chest or respiratory)).mp. or (lung adj3 (shock or failure or injury)).mp. or (pulmonary adj3 capillary leak*).mp.
2. exp neuromuscular blocking agent/ or exp muscle relaxant agent/ or (neuromuscular adj3 block*).af.
3. 1 and 2
4. (placebo.sh. or controlled study.ab. or random*.ti,ab. or trial*.ti,ab. or ((singl* or doubl* or trebl* or tripl*) adj3 (blind* or mask*)).ti,ab.) not (animals not (humans and animals)).sh.
5. 3 and 4

Appendix 4. Study selection form

First authorJournal/Conference Proceedings, etcYear
   

Appendix 5. Study eligibility

Study characteristics Eligibility criteriaYesNoUnclear

Location in text

(pg & ¶/fig/table)

Type of studyRandomized controlled trial    
Participants

Inclusion criteria

  • All ARDS patients (PaO2/FiO2 ratio ≤ 300 mm Hg at a PEEP ≥ 5 cm H2O) who are receiving appropriate sedation (the sedation level varies according to the medical condition of individual patients) and mechanical ventilation

Exclusion criteria

  • Participants who have clinical evidence of left atrial hypertension. We will also exclude severe chronic respiratory disease requiring long-term oxygen therapy or mechanical ventilation

    
Types of interventions

Intervention group: conventional therapy plus non-depolarizing NMBA; Control group: conventional therapy plus placebo (types of placebo will vary according to different studies)

Or intervention group: conventional therapy plus non-depolarizing NMBA; Control group: conventional therapy

Conventional therapy is defined as treatment when possible of the underlying cause, mechanical ventilation, strict control input of liquid, multi-organ support, appropriate antimicrobial therapy and early enteral nutrition

    
Types of outcome measuresSurvival rate, ICU-acquired paresis, PaO2/FiO2 ratio, ventilator-free days, days outside the ICU, relative inflammatory factors, days without organ failure, barotraumas    
INCLUDE EXCLUDE
Reason for exclusion 
Notes:

Do not proceed if any of the above answers is 'No'. If the study is to be excluded, record below the information to be inserted into 'Table of excluded studies'.

Appendix 6. Eligible trials form

Code each paperAuthor(s)Journal/Conference proceedings, etcYear
    
    

Appendix 7. Data extraction form

Review title or ID
 

1. General information

Date form completed (dd/mm/yyyy) 
Name/ID of person extracting data 

Report title

(title of paper/abstract/report from which data are extracted)

 

Report ID

(ID for this paper/abstract/report)

 
Report author contact details 

Publication type

(e.g. full report, abstract, letter)

 
Notes:

2. Participant characteristics

Participant characteristics

Description as stated in report/paper

(provide overall data and, if available, comparative data for each intervention or comparison group)

Location in text

(pg & ¶/fig/table)

Age (mean, median, range, etc)  
Sex of participants (numbers/%, etc)  
Severity of illness  
Comorbidities  
Other  
Notes:

3. Trial characteristics

Trial characteristics

Description as stated in report/paper

(provide overall data and, if available, comparative data for each intervention or comparison group)

Location in text

(pg & ¶/fig/table)

Aim of study  
Country/Countries  
Single centre/Multicentre  
Setting (including location and social context)  
Population description (from which study participants are drawn)  
How was participant eligibility defined?  
How many people were randomly assigned?  
Number of participants in each intervention group  
Number of participants who received intended treatment  
Number of participants who were analysed  
Intervention treatment used  
Dose/Frequency of administration  
Duration of treatment (state hours/days)  
Other treatment received (additional to study intervention)  
Length of follow-up reported in this paper (state days, weeks, months or years if not stated)  
Other  
Notes:

4. Outcomes (Copy and paste table for each outcome, including additional tables for each time point and subgroup as required)

Dichotomous outcome

  Description as stated in report/paper

Location in text

(pg & ¶/fig/table)

Outcome name  

Outcome definition

(with diagnostic criteria if relevant)

  

Unit of measurement

(if relevant)

  
Time points measured  
Time points reported  
Results Intervention Comparison 
No. eventsNo. participantsNo. eventsNo. participants
    
No. missing participants and reasons   

Imputation of missing data

(e.g. assumptions made for ITT analysis)

   

Statistical methods used and appropriateness of these methods

(e.g. adjustment for correlation)

  
Notes:

Continuous outcome

  Description as stated in report/paper

Location in text

(pg & ¶/fig/table)

Outcome name  

Outcome definition

(with diagnostic criteria if relevant)

  

Unit of measurement

(if relevant)

  
Time points measured  
Time points reported  
Results Intervention Comparison 
MeanSD (or other variance)No. participantsMeanSD (or other variance)No. participants
      
No. missing participants and reasons     

Imputation of missing data

(e.g. assumptions made for ITT analysis)

     

Statistical methods used and appropriateness of these methods

(e.g. adjustment for correlation)

  
Notes:

Appendix 8. Risk of bias assessment

Domain Risk of bias Support for judgement
Low riskHigh riskUnclear

Random sequence generation

(selection bias)

    

Allocation concealment

(selection bias)

    

Blinding of participants and personnel

(performance bias)

    

Blinding of outcome assessment

(detection bias)

    

Incomplete outcome data

(attrition bias)

    

Selective outcome reporting?

(reporting bias)

    
Other bias    
Notes:

Contributions of authors

Conceiving of the review: Zhuo Guangying (ZG)

Co-ordinating the review: ZG

Screening search results: ZG, Li J Yang (LJY)

Organizing retrieval of papers: ZG, LJY

Screening retrieved papers against inclusion criteria: ZG, Qing He (QH), LJY

Appraising quality of papers: ZG, LJY

Abstracting data from papers: ZG, LJY

Writing to authors of papers for additional information: ZG, LJY

Providing additional data about papers: ZG, LJY

Obtaining and screening data on unpublished studies: ZG, LJY

Providing data management for the review: ZG, LJY

Entering data into Review Manager (RevMan 5.1): ZG

Handling RevMan statistical data: Guan J Liu (GJL)

Performing other statistical analysis not using RevMan: ZG, GJL

Interpreting data: ZG, QH

Making statistical inferences: GJL, ZG, QH

Writing the review: ZG, QH, Jonathan N Rajan (JAR)

Performing previous work that provided the foundation for the present study: ZG

Serving as guarantor for the review (one review author): ZG

Taking responsibility for reading and checking the review before submission: ZG, QH, JAR

Declarations of interest

Zhuo Guangying: none known.

Qing He: none known.

Li J Yang: none known.

Guan J Liu: none known.

Jonathan N Rajan: none known.

Sources of support

Internal sources

  • West China Hospital, Sichuan University, China.

    Financial support

External sources

  • No sources of support supplied

Ancillary