Pharmacological agents for adults with acute respiratory distress syndrome

Sharon R Lewis; Michael W Pritchard; Carmel M Thomas; Andrew F Smith

doi:10.1002/14651858.CD004477.pub3

. 2019 Jul 23;2019(7):CD004477. doi: 10.1002/14651858.CD004477.pub3

Pharmacological agents for adults with acute respiratory distress syndrome

Sharon R Lewis ^1,^✉, Michael W Pritchard ¹, Carmel M Thomas ², Andrew F Smith ³

Editor: Cochrane Emergency and Critical Care Group

PMCID: PMC6646953 PMID: 31334568

Abstract

Background

Acute respiratory distress syndrome (ARDS) is a life‐threatening condition caused by direct or indirect injury to the lungs. Despite improvements in clinical management (for example, lung protection strategies), mortality in this patient group is at approximately 40%. This is an update of a previous version of this review, last published in 2004.

Objectives

To evaluate the effectiveness of pharmacological agents in adults with ARDS on mortality, mechanical ventilation, and fitness to return to work at 12 months.

Search methods

We searched CENTRAL, MEDLINE, Embase, and CINAHL on 10 December 2018. We searched clinical trials registers and grey literature, and handsearched reference lists of included studies and related reviews.

Selection criteria

We included randomized controlled trials (RCTs) comparing pharmacological agents with control (placebo or standard therapy) to treat adults with established ARDS. We excluded trials of nitric oxide, inhaled prostacyclins, partial liquid ventilation, neuromuscular blocking agents, fluid and nutritional interventions and medical oxygen. We excluded studies published earlier than 2000, because of changes to lung protection strategies for people with ARDS since this date.

Data collection and analysis

Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.

Main results

We included 48 RCTs with 6299 participants who had ARDS; two included only participants with mild ARDS (also called acute lung injury). Most studies included causes of ARDS that were both direct and indirect injuries. We noted differences between studies, for example the time of administration or the size of dose, and because of unclear reporting we were uncertain whether all studies had used equivalent lung protection strategies.

We included five types of agents as the primary comparisons in the review: corticosteroids, surfactants, N‐acetylcysteine, statins, and beta‐agonists. We included 15 additional agents (sivelestat, mesenchymal stem cells, ulinastatin, anisodimine, angiotensin‐converting enzyme (ACE) inhibitor, recombinant human ACE2 (palifermin), AP301, granulocyte‐macrophage colony stimulating factor (GM‐CSF), levosimendan, prostacyclins, lisofylline, ketaconazole, nitroglycerins, L‐2‐oxothiazolidine‐4‐carboxylic acid (OTZ), and penehyclidine hydrochloride).

We used GRADE to downgrade outcomes for imprecision (because of few studies and few participants), for study limitations (e.g. high risks of bias) and for inconsistency (e.g. differences between study data).

Corticosteroids versus placebo or standard therapy

Corticosteroids may reduce all‐cause mortality within three months by 86 per 1000 patients (with as many as 161 fewer to 19 more deaths); however, the 95% confidence interval (CI) includes the possibility of both increased and reduced deaths (risk ratio (RR) 0.77, 95% CI 0.57 to 1.05; 6 studies, 574 participants; low‐certainty evidence). Due to the very low‐certainty evidence, we are uncertain whether corticosteroids make little or no difference to late all‐cause mortality (later than three months) (RR 0.99, 95% CI 0.64 to 1.52; 1 study, 180 participants), or to the duration of mechanical ventilation (mean difference (MD) −4.30, 95% CI −9.72 to 1.12; 3 studies, 277 participants). We found that ventilator‐free days up to day 28 (VFD) may be improved with corticosteroids (MD 4.09, 95% CI 1.74 to 6.44; 4 studies, 494 participants; low‐certainty evidence). No studies reported adverse events leading to discontinuation of study medication, or fitness to return to work at 12 months (FTR).

Surfactants versus placebo or standard therapy

We are uncertain whether surfactants make little or no difference to early mortality (RR 1.08, 95% CI 0.91 to 1.29; 9 studies, 1338 participants), or whether they reduce late all‐cause mortality (RR 1.28, 95% CI 1.01 to 1.61; 1 study, 418 participants). Similarly, we are uncertain whether surfactants reduce the duration of mechanical ventilation (MD −2.50, 95% CI −4.95 to ‐0.05; 1 study, 16 participants), make little or no difference to VFD (MD −0.39, 95% CI −2.49 to 1.72; 2 studies, 344 participants), or to adverse events leading to discontinuation of study medication (RR 0.50, 95% CI 0.17 to 1.44; 2 studies, 88 participants). We are uncertain of these effects because we assessed them as very low‐certainty. No studies reported FTR.

N‐aceytylcysteine versus placebo

We are uncertain whether N‐acetylcysteine makes little or no difference to early mortality, because we assessed this as very low‐certainty evidence (RR 0.64, 95% CI 0.32 to 1.30; 1 study, 36 participants). No studies reported late all‐cause mortality, duration of mechanical ventilation, VFD, adverse events leading to study drug discontinuation, or FTR.

Statins versus placebo

Statins probably make little or no difference to early mortality (RR 0.99, 95% CI 0.78 to 1.26; 3 studies, 1344 participants; moderate‐certainty evidence) or to VFD (MD 0.40, 95% CI −0.71 to 1.52; 3 studies, 1342 participants; moderate‐certainty evidence). Statins may make little or no difference to duration of mechanical ventilation (MD 2.70, 95% CI ‐3.55 to 8.95; 1 study, 60 participants; low‐certainty evidence). We could not include data for adverse events leading to study drug discontinuation in one study because it was unclearly reported. No studies reported late all‐cause mortality or FTR.

Beta‐agonists versus placebo control

Beta‐agonists probably slightly increase early mortality by 40 per 1000 patients (with as many as 119 more or 25 fewer deaths); however, the 95% CI includes the possibility of an increase as well as a reduction in mortality (RR 1.14, 95% CI 0.91 to 1.42; 3 studies, 646 participants; moderate‐certainty evidence). Due to the very low‐certainty evidence, we are uncertain whether beta‐agonists increase VFD (MD −2.20, 95% CI −3.68 to −0.71; 3 studies, 646 participants), or make little or no difference to adverse events leading to study drug discontinuation (one study reported little or no difference between groups, and one study reported more events in the beta‐agonist group). No studies reported late all‐cause mortality, duration of mechanical ventilation, or FTR.

Authors' conclusions

We found insufficient evidence to determine with certainty whether corticosteroids, surfactants, N‐acetylcysteine, statins, or beta‐agonists were effective at reducing mortality in people with ARDS, or duration of mechanical ventilation, or increasing ventilator‐free days. Three studies awaiting classification may alter the conclusions of this review. As the potential long‐term consequences of ARDS are important to survivors, future research should incorporate a longer follow‐up to measure the impacts on quality of life.

Plain language summary

Drugs to treat acute respiratory distress syndrome in adults

We set out to determine, from randomized controlled trials, which drugs improve health outcomes in adults with acute respiratory distress syndrome (ARDS).

Background

ARDS is a life‐threatening condition caused by injury to the lungs, for example from infections such as pneumonia or sepsis, or from trauma. People with ARDS are cared for in an intensive care unit, and need support with breathing from mechanical ventilation. Many people who survive ARDS suffer from muscle weakness, fatigue, reduced quality of life after hospital discharge, and may not be fit for work 12 months later. Despite improvements in techniques to manage ARDS, death rates are still very high. Drugs may help to repair damage to the lung injury, or limit the body's response to the injury (for example, by reducing any excess fluid that may collect around the injured lungs).

Study characteristics

The evidence is current to 10 December 2018. We included 48 studies, of 20 different drug types, involving 6299 people who had ARDS. Three studies are awaiting classification (because we did not have enough details to assess them), and 18 studies are still ongoing. We found differences between included studies, such as the severity of ARDS, or potential differences in clinical management and doses. We excluded studies published before 2000, in order to only include up‐to‐date clinical management of people with ARDS (for example, in the pressure applied during mechanical ventilation). However, we found that many studies did not report these management strategies.

For the main comparisons in this review, we included five types of drugs: corticosteroids, surfactants, N‐acetylcysteine, statins, and beta‐agonists. These were compared to placebo or to standard care.

Key results

Although corticosteroids may reduce the number of people who die within the first three months, and beta‐agonists probably slightly increase these early deaths, we found both an increase and a reduction in deaths in our analyses for these drugs. We found no evidence that surfactants, N‐acetylcysteine, or statins made a difference to the number of people who died within three months. Only two studies (one that assessed steroids, and one surfactants) reported deaths later than three months, but evidence for this was uncertain.

We found that statins or steroids may make little or no difference to the duration of mechanical ventilation, but we were uncertain about the evidence for steroids. Similarly, we were uncertain whether surfactants reduced the use of mechanical ventilation. We found that steroids may improve the number of days that people do not need mechanical ventilation (ventilator‐free days up to day 28), but that beta‐agonists may not improve ventilator‐free days (although we were uncertain about the evidence for beta‐agonists). We found that statins probably make little or no difference to the number of ventilator‐free days; this was also the case for surfactants (although, again, we were uncertain about the evidence for surfactants).

Few studies (and only for surfactants and beta‐agonists) reported whether the study drug was stopped because of serious side effects, and we were uncertain whether either of these drugs led to such serious side effects. No studies reported whether people were fit to return to work 12 months after their illness.

Certainty of the evidence

Most of the findings were supported by low‐ or very low‐certainty evidence, although we were moderately confident in the evidence for some outcomes when statins and beta‐agonists were used. For some outcomes we found too few studies with few participants, and sometimes there were unexplained differences between the studies in their findings. These factors reduced our certainty (or confidence) in our findings. Also, it was not possible to mask some researchers because the study drug was compared to standard therapy (no drug), which may have biased our findings.

Conclusion

We found insufficient evidence to determine confidently whether any type of drug was effective at reducing deaths in people with ARDS, or reducing the length of time that they needed mechanical ventilation. No studies reported fitness to return to work at 12 months. We assessed most outcomes to be low or very low certainty, which reduces our confidence in the findings of the review.

Summary of findings

Background

Description of the condition

Acute respiratory distress syndrome (ARDS), first described in 1967 (Ashbaugh 1967), is characterized by diffuse inflammation of the lung's alveolar‐capillary membrane in response to various pulmonary and extrapulmonary insults (Ware 2000). These insults cause pulmonary injury by direct mechanisms (for example, gastric aspiration, pneumonia, inhalational injury, pulmonary contusion), or indirect mechanisms (for example, sepsis, trauma, pancreatitis, multiple transfusions of blood products). An American‐European Consensus Conference (AECC) formulated a widely‐cited definition of ARDS as follows (Bernard 1994):

an acute onset of hypoxaemia, with a ratio of the partial pressure of arterial oxygen (PaO₂) to the inspired fraction of oxygen (FiO₂) of 200 mmHg or less;
bilateral infiltrates on a frontal chest radiograph;
no clinical evidence of left atrial hypertension or a pulmonary artery occlusion pressure of 18 mmHg or less in the presence of a pulmonary artery catheter.

This AECC definition defined acute lung injury (ALI) as a milder form of lung injury, with a PaO₂/FiO₂ ratio of 300 mmHg or less, with ARDS therefore being a subset of ALI. A more recent definition, known as the Berlin definition, provides a time in which ARDS is developed, and categorizes severity into mild, moderate or severe ARDS, thus removing the distinction between ALI and ARDS (ARDS Definition Task Force 2012). This definition includes the following criteria:

within one week of a known clinical insult or new or worsening respiratory symptoms;
bilateral opacities, not fully explained by effusions, lobar or lung collapse, or nodules;
respiratory failure not fully explained by cardiac failure or fluid overload. Objective assessment (e.g. echocardiography) needed to exclude hydrostatic oedema if no risk factor present;
mild ARDS: PaO₂/FiO₂ > 200 mmHg and ≤ 300 mmHg with positive end‐expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) ≥ 5 cmH₂O;
moderate ARDS: PaO₂/FiO₂ > 100 mmHg and ≤ 200 mmHg with PEEP ≥ 5 cmH₂O;
severe ARDS: PaO₂/FiO₂ ≤ 100 mmHg with PEEP ≥ 5 cmH₂O.

An epidemiological study of 50 countries reported the prevalence of ARDS as 10.4% of all intensive care unit (ICU) admissions, with mortality estimated to be approximately 40% (Bellani 2016). Almost all people with ARDS require mechanical ventilation to survive; all require supplemental oxygen. In addition, survivors have a prolonged stay in the ICU and demonstrate significant functional limitations, primarily fatigue and muscle weakness, that reduce their quality of life after hospital discharge; only 50% of survivors are fit to return to work after 12 months (Herridge 2003).

Description of the intervention

Research on therapy for ARDS has focused on both physiological and pharmacological therapies. Lung protection strategies, using lower tidal volumes (Guay 2018), have been widely adopted since the ARDS Network publication (ARDS Network 2000; Petrucci 2013). Other strategies that have been trialed include high‐frequency oscillatory ventilation (Sud 2016), high versus low PEEP (Santa Cruz 2013), pressure‐controlled versus volume‐controlled ventilation (Chacko 2015), recruitment manoeuvres (Hodgson 2016), and use of prone positioning (Bloomfield 2015).

The pathogenesis of ARDS, extensively reviewed elsewhere (Luce 1998; Ware 2000), provides multiple potential targets for pharmacological interventions. Regardless of the inciting insult, the pathology of ARDS features damage to the alveolar‐capillary membrane, with leakage of protein‐rich oedema fluid into alveoli. Epithelial damage involves the basement membrane and types I and II cells. Injury reduces the amount and function of surfactant produced by type II cells. This increases alveolar surface tension, decreases lung compliance, and causes atelectasis. Endothelial damage is associated with numerous inflammatory events. These include neutrophil recruitment, sequestration and activation; formation of oxygen radicals; activation of the coagulation system, leading to microvascular thrombosis with platelet‐fibrin thrombi; and recruitment of mesenchymal cells with production of procollagen (a precursor to fibrosing alveolitis). Within the alveolar space, the balance between pro‐inflammatory (for example, tumour necrosis factor (TNF) alpha and interleukins (IL) 1, 6, and 8) and anti‐inflammatory mediators (for example, IL‐1 receptor antagonist and soluble TNF receptor) favours ongoing inflammation. In summary, initial lung injury is followed by repair, remodelling, and fibrosing alveolitis.

Interventions in this review are pharmacological agents that aim to repair specific damage or response to the lung injury. These agents may be man‐made, natural, or endogenous (from within the body) and include, amongst others: corticosteroids; surfactants; N‐acetylcysteine; statins; and beta‐agonists.

How the intervention might work

The diversity of approaches to pharmacological therapy for ARDS reflects the complex pathophysiology, and each therapy may differ in its proposed mechanism of action. Of just some of the possible pharmacological agents that may be used to treat the symptoms of ARDS: corticosteroids may provide multiple anti‐inflammatory pathways (Pehora 2017; Polderman 2018); surfactants may restore the normal mechanical properties of alveoli (surface tension, alveolar opening) (Spragg 2003); N‐acetylcysteine may be used for its antioxidant properties (Ortolani 2000); statins may reduce pulmonary and systemic inflammatory responses (HARP‐2 2014); and beta‐agonists may reduce pulmonary oedema and improve alveolar fluid clearance (ALTA 2011).

Why it is important to do this review

Recent guidelines have recommended the use of therapies in relation to lung protection strategies, fluid management strategies, neuromuscular blocking agents (Lundstrøm 2017), positive end‐expiratory pressure (PEEP), extra‐corporeal membrane oxygenation (ECMO), extra‐corporeal carbon dioxide removal (ECCOR), and prone positioning (FICM/ICS Guideline Development Group 2018). This guideline provides a research recommendation for corticosteroids because of insufficient evidence; the range of pharmacological agents in this review are not included in the guideline. The effectiveness of pharmacological agents to reduce mortality or mechanical ventilation is still not established (Nanchal 2018).

This review is an update of a previous version (Adhikari 2004). Research interest in this condition continues, and we aim to incorporate new findings for agents included in the previous version, as well as new agents that were not previously included. The outcomes in the previous version remain relevant, but this review includes consideration of the long‐term consequences and includes fitness to return to work after 12 months (Herridge 2003). The methods used to assess the certainty of evidence in Cochrane Reviews has since been updated, and we reflect these methodological changes and now incorporate a GRADE assessment and 'Summary of findings' tables for the primary comparisons.

Objectives

To evaluate the effectiveness of pharmacological agents in adults with ARDS on mortality, mechanical ventilation, and fitness to return to work at 12 months.

Methods

Criteria for considering studies for this review

Types of studies

We included randomized controlled trials (RCTs). We excluded quasi‐randomized trials.

We excluded studies published prior to 2000. We based the decision to restrict studies by publication date on an important study in 2000 advocating the use of lower tidal volumes in people with ARDS, which resulted in changes to standard practice in mechanical ventilation management for these people (ARDS Network 2000).

Types of participants

We included adult participants with ARDS admitted to an ICU. We used authors' definitions of adult, and included studies if the mean age of participants was more than 18 years. In addition, we used authors' definitions of ARDS, and included participants that were diagnosed according to the AECC criteria, with a distinction between ALI and ARDS (Bernard 1994), and the later Berlin definition which includes a distinction between mild, moderate, and severe ARDS (ARDS Definition Task Force 2012), or other criteria. We excluded studies in which ARDS (and ALI, where appropriate) was not reported as a required study inclusion criterion; we therefore excluded studies in which participants with ARDS were reported as a subgroup analysis.

Types of interventions

We included pharmacological agents compared to a placebo or to no therapy for the treatment of established ARDS, including any pharmacological agent given for the treatment of established mild ARDS (or ALI) that may prevent the development of ARDS. We included pharmacological agents that were man‐made, natural, or endogenous (from within the body).

We excluded enteral and intravenous therapies that are either not considered to be pharmacological by regulatory authorities (nutritional or herbal interventions) or are combined with other management strategies (fluid management). We excluded therapies that have been reviewed in other Cochrane Reviews: inhaled nitric oxide (Gebistorf 2016); inhaled prostacyclins (Afshari 2017); and partial liquid ventilation (Galvin 2013). We excluded pharmacological therapies used as part of a strategy of mechanical ventilation (neuromuscular blocking agents), and medical oxygen. We excluded studies of activated protein C (APC), which is now a withdrawn drug.

We excluded any pharmacological therapy started for prophylaxis of mild ARDS, even when continued in people who subsequently developed moderate or severe ARDS. We excluded studies directly comparing two pharmacological therapies without a no‐treatment or placebo control group.

Each type of agent represented a different comparison, and we separately analysed data for each comparison group. We selected five primary comparisons in the review.

Corticosteroids versus control
Surfactants versus control
N‐acetylcysteine versus control
Statins versus control
Beta‐agonists versus control

We analysed other types of agents as secondary comparison groups.

Types of outcome measures

Primary outcomes

Early all‐cause mortality (at or before three months after randomization). We included ICU and hospital mortality in this outcome.

Secondary outcomes

Late all‐cause mortality (more than three months after randomization).
Duration of mechanical ventilation (defined as the time from randomization to extubation, study withdrawal, or death).
Number of ventilator‐free days to day 28 (Schoenfeld 2002).
Adverse events (defined as those leading to discontinuation of the study medication). In studies with a no‐placebo control arm, adverse events were defined as those leading to discontinuation of the study medication, or 'serious adverse events' using study authors' definitions.
Fitness to return to work at 12 months.

Search methods for identification of studies

Electronic searches

We identified RCTs through literature searching with systematic and sensitive search strategies, as outlined in Chapter 6.4 of theCochrane Handbook of Systematic Reviews of Interventions (Cochrane Handbook;Higgins 2011). We applied no restrictions to language or publication status. We searched the following databases for relevant trials:

Cochrane Central Register of Controlled Trials (CENTRAL; 2018; Issue 12);
MEDLINE (Ovid SP; 1946 to 10 December 2018);
Embase (Ovid SP; 1974 to 10 December 2018);
CINAHL (EBSCOhost: 1937 to 10 December 2018).

We developed a subject‐specific search strategy in MEDLINE and other listed databases. We developed the search strategy in consultation with the Information Specialist for the Cochrane Emergency and Critical Group. Search strategies can be found in: Appendix 1; Appendix 2; Appendix 3; Appendix 4.

We scanned the following clinical trials registers for ongoing and unpublished trials:

World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp/en/) on 18 December 2018);
ClinicalTrials.gov (www.clinicaltrials.gov) on 10 December 2018.

Searching other resources

We carried out citation searching of identified included studies published since 2010 in Web of Science on 7 January 2019 (apps.webofknowledge.com). We conducted a search of grey literature using Opengrey on 7 January 2019 (www.opengrey.eu/). In addition, we scanned reference lists of relevant systematic reviews which were recently published (since 2015). We did not contact content experts to enquire about additional unpublished trails during the 2019 update.

Data collection and analysis

Two review authors (SL and either MP, CT, or AS) independently completed data collection on studies written in English or Spanish before comparing results and reaching consensus. One review author (SL) completed data collection using the English abstract for studies written in Chinese; Dr Henry HL Wu completed full data extraction of the Chinese study reports (Acknowledgements). One review author (AS) was available to resolve conflicts if required.

Selection of studies

We used reference management software to collate the results of searches and to remove duplicates (Endnote). We used Covidence 2018 software to screen results of the search of titles and abstracts and to identify potentially relevant studies. We sourced the full texts of all potentially relevant studies and considered whether they met the inclusion criteria (see Criteria for considering studies for this review). We reviewed abstracts at this stage, and included them in the review only if they provided sufficient information and relevant results that included denominator figures for the intervention and control groups. We recorded the number of papers retrieved at each stage and report this information using a PRISMA flow chart. We reported in the review brief details of closely related but excluded papers.

Data extraction and management

We used Covidence 2018 software to extract data from individual studies. A basic template for data extraction forms is available at www.covidence.org. We adapted this template to include the following information.

Methods: type of study design; setting; dates of study; funding sources and study author declarations of interest.
Participants: number of participants randomized to each group; baseline characteristics (to include: criteria for ARDS diagnosis; time since onset of ARDS; PaO₂:FiO₂ at baseline; risk factors; Lung Injury Score (LIS) (Murray 1988); and illness severity scores such as 'Acute Physiology and Chronic Health Evaluation II' (APACHE II).
Intervention: details of pharmacological intervention and control (to include dose, timing and duration of administration), details of any other treatment. We attempted to collect data on clinical management of participants during the study period, which may influence results; we based this on the current guidelines for the management of ARDS, which includes information about: lower tidal volumes, fluid management strategies, neuromuscular blocking agents, positive end‐expiratory pressure (PEEP), extra‐corporeal membrane oxygenation (ECMO), extra‐corporeal carbon dioxide removal (ECCOR), and prone positioning (FICM/ICS Guideline Development Group 2018).
Outcomes: all relevant review outcomes as measured and reported by study authors, including time points of measurement.
Outcome data: results of outcome data

We considered the applicability of information from individual studies and the generalizability of data to our intended study population (i.e. the potential for indirectness in our review). If we found associated publications from the same study, we created a composite data set based on all eligible publications.

Assessment of risk of bias in included studies

Two review authors (SL and either MP or CT) independently assessed study quality, study limitations, and the extent of potential bias by using the Cochrane 'Risk of bias' tool (Higgins 2017). We assessed the following domains.

Sequence generation (selection bias);
Allocation concealment (selection bias);
Blinding of participants, personnel, and outcome assessors (performance and detection bias);
Incomplete outcome data (attrition bias);
Selective outcome reporting (reporting bias);
Other potential risks of bias.

In addition, we assessed comparability of baseline characteristics between study groups, as characteristics such as illness severity may influence response to treatment. For each domain, we judged whether study authors had made sufficient attempts to minimize bias in their study design. We made judgements using three measures: high; low; and unclear risk of bias. We recorded this judgement in 'Risk of bias' tables and present a summary 'Risk of bias' figure (see Figure 2).

Measures of treatment effect

We collected dichotomous data for mortality outcomes, adverse events, and fitness to return to work. We collected continuous data for duration of mechanical ventilation, and number of ventilator‐free days up to day 28. We reported dichotomous data as risk ratios (RRs) to compare groups, and continuous data as mean differences (MDs). We reported 95% confidence intervals (CI).

Unit of analysis issues

We noted studies that had more than one intervention group. We combined data in intervention groups and compared these combined data with the control group. We used sensitivity analysis to investigate the effect of combining data from more than one intervention group in a study.

Dealing with missing data

We considered data to be complete if losses were reported and explained by study authors, and we combined no incomplete data in the meta‐analysis. We did not contact study authors to clarify missing information about study characteristics.

Assessment of heterogeneity

We assessed whether evidence of inconsistency was apparent in our results by considering heterogeneity. We assessed clinical and methodological heterogeneity by comparing similarities in our included studies between study designs, participants, interventions, and outcomes, and used the data collected from the full‐text reports (as stated in Data collection and analysis). We assessed statistical heterogeneity by calculating the Chi² text or I² statistic and judged any heterogeneity above an I² value or 60% and a Chi² P value of 0.05 or less to indicate moderate to substantial statistical heterogeneity (Higgins 2011).

As well as looking at statistical results, we considered point estimates and overlap of CIs. If CIs overlap, then results are more consistent. However, combined studies may show a large consistent effect but with significant heterogeneity. We therefore planned to interpret heterogeneity with caution (Guyatt 2011a).

Assessment of reporting biases

We attempted to source published protocols for each of our included studies by using clinical trials registers. We compared published protocols with published study results, to assess the risk of selective reporting bias. We planned to generate a funnel plot to assess the risk of publication bias if we identified sufficient studies reporting on an outcome (i.e. more than 10 studies (Sterne 2017)). An asymmetrical funnel plot may suggest publication of only positive results (Egger 1997).

Data synthesis

We completed meta‐analyses of outcomes for which we had comparable effect measures from more than one study for each comparison group, and when measures of heterogeneity indicated that pooling of results was appropriate. We did not pool studies that had a high level of methodological or clinical heterogeneity. We used the statistical calculator in Review Manager 5 to perform meta‐analysis (Review Manager 2014).

We used the Mantel‐Haenszel random‐effects model to account for potential variability in participant conditions between studies.

We calculated CIs at 95% and used a P value of 0.05 or less to judge whether a result was statistically significant. We considered imprecision in the results of analyses by assessing the CI around an effect measure; a wide CI would suggest a higher level of imprecision in our results. A small number of studies may also reduce precision (Guyatt 2011b).

Subgroup analysis and investigation of heterogeneity

We did not perform subgroup analysis because we found insufficient studies in each comparison group (i.e. fewer than 10) to enable meaningful analysis (Deeks 2017). If we had found sufficient studies, we planned to perform subgroup analysis as follows:

severity of ARDS: studies with participants meeting the criteria for mild ARDS versus studies with participants meeting the criteria for moderate ARDS; or studies with participants meeting the criteria for moderate ARDS versus studies with participants meeting the criteria for severe ARDS. We used the more recent Berlin definition of ARDS for these cut‐off points (ARDS Definition Task Force 2012);
time since onset of ARDS: early (72 hours or less) versus late (more than 72 hours).

We reported the information collected for these subgroups for each primary comparison group.

Sensitivity analysis

Although we had tried to include studies that only used current guidelines on the clinical management of ARDS by excluding studies published prior to 2000, we found that studies did not consistently or sufficiently report clinical management protocols. The ARDS Network study published in 2000 demonstrated a reduction in mortality when lower tidal volumes were used (ARDS Network 2000). Studies in which this strategy was not used may therefore not be generalizable to current management of people with ARDS, and we excluded these studies during sensitivity analysis in order to explore this potential effect on the results.

We also explored the potential effect of decisions made as part of the review process. We performed the following sensitivity analysis on our primary outcome (early all‐cause mortality) in our primary comparisons in this review.

We excluded studies in which use of lower tidal volumes was not reported.
We excluded studies that we judged at high or unclear risk of selection bias.
We excluded studies that we judged to have high risk of attrition bias because of missing data which were unbalanced between groups, and unexplained.
We conducted meta‐analysis using the alternative meta‐analytic effects model (i.e. fixed‐effect).
In multi‐arm studies in which data from more than one intervention group were combined, we separately included data for each arm in analysis.

In each sensitivity analysis we compared the effect estimate with the main analysis. We reported these effect estimates only if they indicated a difference in interpretation of the effect.

Summary of findings' tables and GRADE

One review author (SL) used the GRADE system to assess the certainty of the body of evidence associated with the following outcomes (Guyatt 2008):

early all‐cause mortality (at or before three months after randomization);
late all‐cause mortality (more than three months after randomization);
duration of mechanical ventilation;
number of ventilator‐free days to day 28;
adverse events;
fitness to return to work at 12 months.

The GRADE approach appraises the certainty of a body of evidence based on the extent to which we can be confident that an estimate of effect or association reflects the item being assessed. Evaluation of the certainty of a body of evidence considers within‐study risk of bias, directness of the evidence, heterogeneity of the data, precision of the effect estimates, and risk of publication bias.

We constructed 'Summary of findings' tables using the GRADE profiler software for the following comparisons in this review (GRADEpro GDT):

corticosteroids versus control (Table 1);
surfactants versus control (Table 2);
N‐acetylcysteine versus control (Table 3);
statins versus control (Table 4);
beta‐agonists versus control (Table 5).

Summary of findings for the main comparison. Corticosteroids compared to control for adults with acute lung injury and acute respiratory distress syndrome.

Corticosteroids compared to control for adults with acute respiratory distress syndrome
Population: adults with acute respiratory distress syndrome  Setting: intensive care units in: China; Kuwait; Thailand; and USA Intervention: corticosteroids (methylprednisolone; hydrocortisone; and budesonide  Comparison: control (placebo or standard therapy)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with control	Risk with corticosteroids
Early all‐cause mortality (≤ 3 months) Reported at: day 14; day 28; day 60; and in hospital	Study population		RR 0.77  (0.57 to 1.05)	574  (6 studies)	⊕⊕⊝⊝ Low^a	‐
	374 per 1000	288 per 1000  (213 to 393)
Late all‐cause mortality ( > 3 months) Reported at: 180 days	Study population		RR 0.99  (0.64 to 1.52)	180  (1 study)	⊕⊝⊝⊝ Very low^b	‐
	319 per 1000	315 per 1000  (204 to 484)
Duration of mechanical ventilation Measured in days	In the control group, mean values range from 11.6 days to 20.3 days	MD 4.30 days lower  (9.72 days lower to 1.12 days higher)	‐	277  (3 studies)	⊕⊝⊝⊝ Very low^c	We did not include 1 additional study (91 participants) in the analysis because data were reported as median values; study authors reported a shorter duration of mechanical ventilation with corticosteroids use
Ventilator‐free days up to day 28	In the control group, mean values range from 6.8 days to 12.8 days	MD 4.09 days higher  (1.74 higher to 6.44 higher)	‐	494  (4 studies)	⊕⊕⊝⊝ Low^d	‐
Adverse events Defined as leading to discontinuation of study medication; or for studies with standard care control, defined by study authors as "serious adverse events"	‐	‐	Not estimable	‐	‐	No studies reported or measured this outcome
Fitness to return to work at 12 months	‐	‐	Not estimable	‐	‐	No studies reported or measured this outcome
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; RR: risk ratio; MD: mean difference
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Surfactants compared to control for adults with acute respiratory distress syndrome
Population: adults with acute respiratory distress syndrome  Setting: intensive care units in: Austria, Belgium; Canada; Cuba; Europe (one multicentre study did not report countries within Europe); Finland; France; Germany; Greece; Netherlands; Norway; South Africa; Spain; Sweden; UK; USA  Intervention: surfactants (surfacen; HL10; venticute; alveofact; calfactant)  Comparison: control (placebo or standard therapy)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
	Risk with control	Risk with surfactants
Early all‐cause mortality (≤ 3 months) Reported at: 28 days; and 90 days. Time point not reported in 4 studies	Study population		RR 1.08  (0.91 to 1.29)	1338  (9 studies)	⊕⊝⊝⊝ Very low^a	‐
	284 per 1000	307 per 1000  (259 to 367)
Late all‐cause mortality ( > 3 months) Reported at: 180 days	Study population		RR 1.28  (1.01 to 1.61)	418  (1 study)	⊕⊝⊝⊝ Very low^b	‐
	362 per 1000	463 per 1000  (366 to 583)
Duration of mechanical ventilation Measured in days	In the control mean duration was 8.1 days	MD 2.5 days lower  (4.95 days lower to 0.05 days lower)	‐	16  (1 study)	⊕⊝⊝⊝ Very low^c	We did not include 1 additional study (48 participants) in analysis because values of data (mean or median) were unclear; study authors reported little or no difference between groups in duration of mechanical ventilation
Ventilator‐free days up to day 28	In the control group, mean values range from 11.9 days to 13 days	MD 0.39 days lower  (2.49 days lower to 1.72 days higher)	‐	344  (2 studies)	⊕⊝⊝⊝ Very low^d	We did not include 4 additional studies (512 participants) in analysis because data were not reported sufficiently; 3 studies reported little or no difference between groups, and 1 study reported more ventilator‐free days in the intervention group
Adverse events Defined as leading to discontinuation of study medication; data collected during study period	Study population		RR 0.50 (0.17 to 1.44)	88 (2 studies)	⊕⊝⊝⊝ Very low^e	‐
	216 per 1000	108 per 1000 (37 to 311)
Fitness to return to work at 12 months	‐		Not estimable			No studies reported or measured this outcome
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; RR: risk ratio; MD: mean difference
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

N‐acetylcysteine compared to control for adults with acute respiratory distress syndrome
Population: adults with acute respiratory distress syndrome  Setting: intensive care unit in: Italy  Intervention: N‐acetylcysteine  Comparison: control (placebo)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with control	Risk with N‐acetylcysteine	Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Early all‐cause mortality (≤ 3 months) Reported at: 30 days	Study population		RR 0.64  (0.32 to 1.30)	36  (1 study)	⊕⊝⊝⊝ Very low^a	‐
	583 per 1000	373 per 1000  (187 to 758)	RR 0.64  (0.32 to 1.30)	36  (1 study)	⊕⊝⊝⊝ Very low^a	‐
Late all‐cause mortality ( > 3 months	‐	‐	Not estimable	‐	‐	No studies measured or reported this outcome
Duration of mechanical ventilation	‐	‐	Not estimable	‐	‐	No studies measured or reported this outcome
Ventilator‐free days up to day 28	‐	‐	Not estimable	‐	‐	No studies measured or reported this outcome
Adverse events Defined as leading to discontinuation of study medication	‐	‐	Not estimable	‐	‐	No studies measured or reported this outcome
Fitness to return to work at 12 months	‐	‐	Not estimable	‐	‐	No studies measured or reported this outcome
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence  High certainty: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Statins compared to control for adults with acute respiratory distress syndrome
Population: adults with acute respiratory distress syndrome  Setting: intensive care units in: Northern Ireland; UK; USA  Intervention: statins (simvastatin; and rosuvastatin)  Comparison: control (placebo)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with control	Risk with statins	Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Early all‐cause mortality (≤ 3 months) Reported at: 60 days; and during hospital stay	Study population		RR 0.99  (0.78 to 1.26)	1344  (3 studies)	⊕⊕⊕⊝ Moderate^a	‐
	262 per 1000	259 per 1000  (204 to 330)	RR 0.99  (0.78 to 1.26)	1344  (3 studies)	⊕⊕⊕⊝ Moderate^a	‐
Late all‐cause mortality ( > 3 months	‐	‐	Not estimable	‐	‐	No studies measured or reported this outcome
Duration of mechanical ventilation Measured in days	In the control group, mean duration was 15.9 days	MD 2.70 days higher (0.35 days lower to 8.95 days higher)	‐	60 (1 study)	⊕⊕⊝⊝ Low^b	‐
Ventilator‐free days up to day 28	In the control group, mean values range from 9.1 days to 15.1 days	MD 0.40 days higher  (0.71 days lower to 1.52 days higher)	‐	1342  (3 studies)	⊕⊕⊕⊝ Moderate^c	‐
Adverse events Defined as leading to discontinuation of study medication	‐	‐	Not estimable	‐	‐	One study measured discontinuation of treatment because of an adverse event, but data were not reported by study authors
Fitness to return to work at 12 months	‐	‐	Not estimable	‐	‐	No studies measured or reported this outcome
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; RR: risk ratio; MD: mean difference
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect  Very low certainty: we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect

Beta‐agonist compared to control for adults with acute respiratory distress syndrome
Population: adults with acute respiratory distress syndrome  Setting: intensive care units in: UK; and USA  Intervention: beta‐agonist (salbutamol; and albuterol)  Comparison: control (placebo)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Outcomes	Risk with control	Risk with beta‐agonist	Relative effect  (95% CI)	Number of participants  (studies)	Certainty of the evidence  (GRADE)	Comments
Early all‐cause mortality (≤ 3 months) Reported at: 28 days; 60 days; and during hospital stay	Study population		RR 1.14  (0.91 to 1.42)	646  (3 studies)	⊕⊕⊕⊝ Moderate^a	‐
	283 per 1000	323 per 1000  (258 to 402)	RR 1.14  (0.91 to 1.42)	646  (3 studies)	⊕⊕⊕⊝ Moderate^a	‐
Late all‐cause mortality (> 3 months	‐	‐	‐	‐	‐	No studies measured or reported this outcome
Duration of mechanical ventilation	‐	‐	Not estimable	‐	‐	No studies measured or reported this outcome
Ventilator‐free days up to day 28	In the control group, mean values range from 5.3 days to 16.6 days	MD 2.20 days lower  (3.68 days lower to 0.71 days lower)	‐	646  (3 studies)	⊕⊝⊝⊝ Very low^b	‐
Adverse events Defined as leading to discontinuation of study medication; data collected during study period	‐	‐	‐	606 (2 studies)	⊕⊝⊝⊝ Very low^c	We did not pool data in 2 studies because of potential differences in types of adverse events. 1 study reported little or no difference between groups; and 1 study reported more adverse events when participants were given beta‐agonists
Fitness to return to work at 12 months	‐	‐	Not estimable	‐	‐	No studies measured or reported this outcome
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; RR: risk ratio; MD: mean difference
GRADE Working Group grades of evidence  High certainty: we are very confident that the true effect lies close to that of the estimate of the effect  Moderate certainty: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low certainty: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect  Very low certainty: we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect

Corticosteroids versus placebo or standard care: late all‐cause mortality
Study ID	Intervention group, n/N	Control group, n/N	Effect estimate*
Steinberg 2006	28/89	29/91	RR 0.99 (95% CI 0.64 to 1.52)
Surfactants versus control: late all‐cause mortality
Study ID	Intervention group, n/N	Control group, n/N	Effect estimate*
Kesecioglu 2009	96/208	76/210	RR 1.28 (95% CI 1.01 to 1.61)
Surfactants versus control: duration of mechanical ventilation
Study ID	Intervention group, mean (SD)/N	Control group, mean (SD)/N	Effect estimate*
Tsangaris 2007	5.6 days (± 2.6 days)/8	8.1 days (± 2.4 days)/8	MD −2.50 (95% CI −4.95 to −0.05)
N‐acetylcysteine versus placebo: early all‐cause mortality
Study ID	Intervention group, n/N	Control group, n/N	Effect estimate*
Ortolani 2000	9/24	7/12	RR 0.64 (95% CI 0.32 to 1.30)
Statins versus placebo: duration of mechanical ventilation
Study ID	Intervention group, mean (SD)/N	Control group, mean (SD)/N	Effect estimate*
HARP 2011	18.6 (± 14.6) days/30	15.9 (± 9.6) days/30	MD 2.70 (95% CI ‐3.55 to 8.95)

Date	Event	Description
6 February 2019	New search has been performed	Title of review changed New review authors added to replace previous author team Minor changes to search strategy. Searches re‐run Studies excluded if published prior to 2000. We have therefore excluded 23 studies from the previous version of the review (Adhikari 2004) New outcome added (fitness to return to work after 12 months) New findings incorporated into review Review updated to incorporate all standard subheadings, and 'Summary of findings' tables added for primary comparisons
6 February 2019	New citation required but conclusions have not changed	New studies, with different pharmacological agents, included in the review update. Overall conclusions continue to show little or no difference in outcomes, with uncertainty in the effects
13 December 2018	Amended	Editorial team changed to Cochrane Emergency and Critical Care
9 June 2010	Amended	Contact details updated.
2 August 2008	Amended	Converted to new review format.

Corticosteroids versus control
Study ID	Comparison	Dose	Time of ARDS onset	Baseline PaO₂/PaO₂ _{Mean (SD)}	Lower tidal volumes
Liu 2012	Hydrocortisone vs placebo	100 mg IV; 3 times daily for 7 days	< 72 h	NR	Yes
Meduri 2007	Methylprednisolone vs placebo	1mg/kg loading dose; 240 mL normal saline at 10 mL/h of 1 mg/kg/day daily infusion for 14 days; halving of doses on day 15, 22 and 26, up to day 28	< 72 h	I: 118.4 (± 51.2) mmHg C: 125.9 (± 38.6) mmHg	Yes*
Rezk 2013	Methylprednisolone vs placebo	1 mg/kg loading dose; 240 mL normal saline at 10 mL/h of 1 mg/kg/day daily infusion for 14 days; halving of doses on day 15, 22 and 26, up to day 28	< 48 h	NR	NR
Steinberg 2006	Methylprednisolone vs placebo	2 mg/kg loading dose; 50 mL of 5% dextrose in water of 0.5 mg/kg; daily infusion every 6 h for 14 days; followed by 0.5 mg/kg every 12 h for 7 days, then tapering of dose over 4 days	7 to 28 days	I: 126 (± 42) mmHg C:126 (± 40) mmHg	Yes*
Tongyoo 2016	Hydrocortisone vs placebo	50 mg in 10 mL normal saline, IV bolus; every 6 h for 7 days	< 12 h	I: 175.4 (± 6.9) mmHg C: 172.4 (± 6.7) mmHg	Yes
Zhao 2014	Budesonide vs standard care	2 mg, inhaled; twice a day for 12 days	NR	NR	Yes
Surfactants versus control
Study ID	Comparison	Dose	Time of ARDS onset	Baseline PaO₂/FiO₂ _{Mean (SD)}	Lower tidal volumes
Barrese‐Perez 2015	Surfacen vs standard therapy	100 mg; every 8 h for 3 days	< 24 h	NR	NR
Kesecioglu 2001	HL‐10 vs standard therapy	100 ‐ 200 mg/kg of phospholipids; up to 4 doses	NR	I: 181 (± 91) mmHg C: 175 (± 72) mmHg	NR
Kesecioglu 2009	HL10 vs standard therapy	100 mL vials of 3 mg HL10 in 60 mL warm saline; 3 boluses at 0 h, 12 h, and 36 h	< 60 h	I: 156.7 (± 54.8) mmHg C: 161.4 (± 55.2) mmHg	Yes
Spragg 2002a	Venticute vs placebo	1 mL/kg; up to 4 doses in 12 to 24 h	NR	NR	NR
Spragg 2002b	Venticute vs placebo	1 mL/kg; up to 4 doses in 12 to 24 h	NR	NR	NR
Spragg 2003	venticute (high dose) vs venticute (low dose) vs standard therapy	High dose: 1 mL/kg; up to 4 doses in 24 h Low dose: 0.5 mL/kg; up to 4 doses in 24 h	< 48 h	I (high): 133.6 (± 8.9) mmHg C (low): 113.9 (± 8.3) mmHg C: 120.9 (± 6.5) mmHg	NR
Tsangaris 2007	Alveofact vs standard therapy	(200/19) mg/kg body weight	< 48 h	I: 100 (± 20) mmHg C: 103 (± 14) mmHg	Yes
Walmrath 2000	Venticute vs standard therapy	1 mL/kg; up to 4 doses in 24 h	NR	NR	NR
Willson 2015	Pneumasurf vs placebo	30 mg/cm of height; up to 3 doses, 12 h apart	< 48 h	NR	Yes
N‐acetylcysteine versus control
Study ID	Comparison	Dose	Time of ARDS onset	Baseline PaO₂/FiO₂ _{mean (SD)}	Lower tidal volumes
Ortolani 2000	NAC vs NAC + rutin vs placebo	50 mg/kg NAC (+ 5 mg/kg rutin); IV every 8 h	< 24 h	NR	NR
Statins versus control
Study ID	Comparison	Dose	Time of ARDS onset	Baseline PaO₂/FiO₂ _{mean (SD)}	Lower tidal volumes
HARP 2011	Simvastatin vs placebo	80 mg; daily for 14 days	< 48 h	I: 173 (± 47) mmHg C: 166 (± 60) mmHg	No (mean tidal volumes, 8.5 mmHg)
HARP‐2 2014	Simvastatin vs placebo	80 mg; daily for up to 28 days	< 48 h	I: 123 (± 54.8) mmHg C: 132.4 (± 55.4) mmHg	Yes
SAILS 2014	Rosuvastatin vs placebo	40 mg loading dose; then 20 mg daily; for up to 28 days	< 48 h	I: 170 (± 71) mmHg C: 170 (± 67) mmHg	Yes
Beta‐agonists versus control
Study ID	Comparison	Dose	Time of ARDS onset	Baseline PaO₂/FiO₂  _{mean (SD)}	Lower tidal volumes
ALTA 2011	Albuterol vs placebo	5.0 mg in saline; aerosolized; very 4 h for up to 10 days	NR	I: 170 (± 84) mmHg C: 170 (± 84) mmHg	Yes
BALTI 2006	Salbutamol vs placebo	0.2 mg/mL; IV 0.075 mL/kg/h; for 7 days	< 48 h	I: 15.6 (± 6.6) kPa C: 13.7 (± 4.9) kPa	NR
BALTI‐2 2013	Salbutamol vs placebo	IV; 0.075 mL/kg/h; for 7 days	< 72 h	I: 103.5 (± 36.75) mmHg I: 103.5 (± 36.75) mmHg	Yes
Footnotes: Lung protection strategies were altered part‐way through the study following a publication (ARDS Network 2000); participants recruited after this publication were managed with lower tidal volumes ARDS:* acute respiratory distress syndrome; C: control group; I: intervention group; IV: intravenous; NAC: N‐acetylcysteine; NR: not reported; PaO₂/FiO₂: ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; SD: standard deviation

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Early mortality	6	574	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.57, 1.05]
2 Duration of mechanical ventilation	3	277	Mean Difference (IV, Random, 95% CI)	‐4.30 [‐9.72, 1.12]
3 Ventilator‐free days up to day 28	4	494	Mean Difference (IV, Random, 95% CI)	4.09 [1.74, 6.44]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Early mortality	9	1338	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.91, 1.29]
2 Ventilator‐free days up to day 28	2	344	Mean Difference (IV, Random, 95% CI)	‐0.39 [‐2.49, 1.72]
3 Adverse events	2	88	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.17, 1.44]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Early mortality	3	1344	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.78, 1.26]
2 Ventilator‐free days up to day 28	3	1342	Mean Difference (IV, Random, 95% CI)	0.40 [‐0.71, 1.52]

Methods	RCT Parallel design
Participants	Total number of randomized participants: 326 Inclusion criteria: intubated and mechanically ventilated; ≥16 years of age; within 72 hours of ARDS onset; ARDS according to AECC (Bernard 1994) Exclusion criteria: pregnancy; current treatment with intravenous beta‐2‐agonist or need for continuous, regular aerosolized beta‐2‐agonists; current treatment with beta‐adrenergic antagonists; imminent withdrawal of medical treatment; chronic liver disease; enrolment in another trial of an investigational medicinal product within previous 28 days Baseline characteristics Intervention group (beta‐agonists) Age, mean (SD): 55.8 (± 17.2) years Gender, M/F: 102/60 APACHE II, mean (SD): 19.5 (± 6.2) PaO₂/FiO₂, mean (SD): 103.5 (± 36.75) mmHg Risk factors: direct ‐ smoke or toxin inhalation 1, aspiration of gastric contents 6, near drowning 1, thoracic trauma 5, pneumonia 86, drug‐related 2, other 2, missing 1; indirect ‐ sepsis 39, cardiopulmonary bypass 1, pancreatitis 6, non‐thoracic trauma 2, transfusion‐related 6, other 4 Control group (placebo) Age, mean (SD): 54.2 (± 17.5) years Gender, M/F: 110/54 APACHE II, mean (SD): 18.9 (± 6.7) PaO₂/FiO₂, mean (SD): 103.5 (± 36.75) mmHg Risk factors: direct ‐ smoke or toxin inhalation 2, aspiration of gastric contents 9, near drowning 0, thoracic trauma 9, pneumonia 79, drug‐related 1, other 5, missing 0; indirect ‐ sepsis 47, cardiopulmonary bypass 1, pancreatitis 4, non‐thoracic trauma 6, transfusion‐related 1, other 0 Country: UK Setting: multicentre; 46 ICUs
Interventions	Intervention group (beta‐agonists) Participants: n = 162; losses = 1 (withdrew consent); analysed = 161 Details: IV salbutamol (beta‐agonist); at a rate of 0.075 mL/kg ideal bodyweight per hour Additional details: in both groups, use of a lung protective‐ventilation strategy (ARDS Network 2000), fluid restriction (Wiedemann 2006), appropriate high PEEP (Brower 2004) Control group (placebo) Participants: n = 164; losses = 1 (withdrew consent); analysed = 163 Details: placebo; 0·9% saline
Outcomes	Outcomes measured/reported: mortality (at day 28); mortality in ICU or hospital; ventilator‐free and organ failure‐free days (up to day 28); length of stay in ICU and hospital; tachycardia; new arrhythmia; other side effects sufficient to stop treatment of trial drug Outcomes relevant to the review: mortality (at day 28, in ICU, in hospital); ventilator‐free days up to day 28; adverse events (tachycardia sufficient to stop study treatment; new arrhythmia sufficient to stop study treatment; new lactic acidosis sufficient to stop study treatment; serious adverse events related to study drug)
Notes	Funding/declarations of interest: UK Medical Research Council, UK Department of Health, UK Intensive Care Foundation; some authors have received investigator‐led research grants, and fees for lectures etc. from pharmaceutical companies ‐ all unrelated to beta‐agonists. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report Study dates: December 2006 to March 2010 Note: trial stopped early due to increased mortality in salbutamol group; decision made by Data Monitoring and Ethics Committee
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Sequence generation (selection bias)	Low risk	Quote: "We used a computer‐generated randomisation sequence with a block size of eight"
Allocation concealment (selection bias)	Low risk	Use of external randomization service
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "Participants, care providers, and investigators were masked to group assignment"
Blinding of outcome assessors for mortality (detection bias)	Low risk	We assumed that outcome assessors were blinded
Blinding of outcome assessors for other outcomes (detection bias)	Low risk	We assumed that outcome assessors were blinded
Incomplete outcome data (attrition bias)   All outcomes	Low risk	2 withdrawals, and 2 not given study drug but small number of losses and ITT analysis used. Trial was stopped early due to increased mortality in salbutamol group; decision made by Data Monitoring and Ethics Committee
Selective outcome reporting (reporting bias)	Low risk	Prospective clinical trials registration (ISRCTN38366450). All outcomes presented in full report
Baseline characteristics	Low risk	All comparable
Other sources of bias	Low risk	None identified

Methods	RCT Parallel design
Participants	Total number of randomized participants: 30 Inclusion criteria: with acute lung injury induced by severe heatstroke; fulfilling criteria listed in Society of Critical Care Medicine of PLAs 2015 Guideline for standardized diagnosis of heatstroke Exclusion criteria: < 16 years of age; hospital stay > 24 hours; brain stem death; COPD patients Baseline characteristics Intervention group (Ulinastatin) Age, mean (SD): 35.1 (± 13.8) years Gender, M/F: 11/4 Apache II, mean (SD): 21.33 (± 4.72) Murray Score, mean (SD): 2.23 (± 0.73) Risk factor: heatstroke Control group (standard therapy) Age, mean (SD): 31.7 (± 15.0) Gender, M/F: 14:1 Apache II, mean (SD): 21.20 (± 4.71) Murray Score, mean (SD): 2.28 (± 0.63) Risk factor: heatstroke Country: China Setting: multicentre; 2 hospitals
Interventions	Intervention group (ulinastatin) Participants: n = 15; losses = 0; analysed = 15 Details: IV ulinastatin with conventional treatment; 200,000 units plus 100 ml saline twice a day for 5 days Additional details: lower tidal volume used in both groups Control group (standard therapy) Participants: n = 15; losses = 0; analysed = 15 Details: conventional treatment: antibiotic prophylaxis; simple analgesia; nutritional support; haemodialysis; mechanical ventilation Additional details: same as intervention group
Outcomes	Outcomes measured/reported: duration of mechanical ventilation; length of ICU stay; mortality (at 28 days); concentration of TNF‐alpha and IL‐6 in BALF and alveolar macrophage supernatant before and after treatment; expression levels of TREM‐1 protein and mRNA in alveolar macrophage after treatment Outcomes relevant to the review: duration of mechanical ventilation; mortality (at 28 days)
Notes	Funding/declarations of interest: National Natural Science Youth Fund; Guangdong Province Medical Research Fund; Dongguan Social Science and Technology Project Fund Study dates: January 2013 to October 2016
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Sequence generation (selection bias)	Low risk	Investigators used computer randomization
Allocation concealment (selection bias)	Unclear risk	No details
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Control is standard therapy and therefore blinding not possible
Blinding of outcome assessors for mortality (detection bias)	Low risk	No blinding of outcome assessors. However, we did not expect this to influence outcome data for mortality
Blinding of outcome assessors for other outcomes (detection bias)	High risk	No blinding of outcome assessors
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No apparent losses
Selective outcome reporting (reporting bias)	Unclear risk	Study authors did not report a pre‐published protocol or clinical trials registration number and therefore we were unable to assess risk of selective outcome reporting bias
Baseline characteristics	Low risk	Appear comparable
Other sources of bias	Low risk	No other source of bias identified

Methods	RCT Parallel design
Participants	Total number of randomized participants: 50 Inclusion criteria: traumatic ALI/ARDS patients whose diagnoses were in accordance with the diagnostic criteria on ALI/ARDS of the Society of Critical Care Medicine of Chinese Medical Association (SCCMCMA 2006) Exclusion criteria: no details Baseline characteristics Intervention group (anisodimine) Age, mean: 48.39 years Gender, M/F: 19/7 APACHE II, mean (SD): 21.83 (± 5.59) PaO₂/FiO₂, mean (SD): 184.6 (± 7.9) mmHg Risk factor: direct and indirect ‐ trauma Control (standard therapy) Age, mean: 45.69 years Gender, M/F: 18/6 APACHE II, mean (SD): 20.87 (± 5.73) PaO₂/FiO₂, mean (SD): 187.7 (± 8.4) mmHg Risk factor: direct and indirect ‐ trauma Country: China Setting: single‐centre; ICU
Interventions	Intervention group (anisodimine) Participants: n = 26; losses = 0; analysed = 26 Details: IV anisodimine; 0.5 mg/kg; 10 to 20 mg given every 30 to 60 minutes according to heart rate; treatment for 3 to 5 days Additional details: mechanical ventilation mode was the same for each group Control group (standard therapy) Participants: n = 24; losses; analysed = 24 Details: no details
Outcomes	Outcomes measured/reported: oxygenation and respiratory variables; mechanical ventilation time; mortality; adverse reactions Outcomes relevant to the review: duration of mechanical ventilation; mortality (time point not reported); adverse reactions (leading to termination of study treatment)
Notes	Funding/declarations of interest: not reported Study dates: January 2009 to October 2011
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Sequence generation (selection bias)	Unclear risk	Participants were "randomly classified". No additional details.
Allocation concealment (selection bias)	Unclear risk	No details
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Compared with standard therapy, therefore not possible to blind personnel to treatment groups
Blinding of outcome assessors for mortality (detection bias)	Low risk	No blinding. However, we did not expect blinding of outcome assessors to influence outcome data for mortality
Blinding of outcome assessors for other outcomes (detection bias)	High risk	No blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No apparent losses
Selective outcome reporting (reporting bias)	Unclear risk	Clinical trials registration or pre‐published protocol not reported. Insufficient information to make judgement.
Baseline characteristics	Low risk	Limited detail but appear balanced between groups
Other sources of bias	Unclear risk	Insufficient detail in paper regarding methodology. No details of 'conventional' therapy used as comparison.

Methods	RCT Parallel design
Participants	Total number of randomized participants: 540 Inclusion criteria: intubated and mechanically ventilated and within 48 hours after onset of ARDS, defined as PaO₂/FiO₂ ≤ 300 mmHg; if bilateral pulmonary oedema was present on chest radiography; if there was no evidence of left atrial hypertension Exclusion criteria: < 16 years of age; not intubated and ventilated; assessed ≥ 48 hours after onset of ARDS; pregnant; elevated creatine kinase level; elevated aminotransferase level; interaction with concomitant drug; severe renal impairment and not receiving RRT; severe liver disease; received statins within previous 2 weeks; required statins for a proven indication; contraindication to enteral drug administration; enrolled in another drug trial; having treatment imminently withdrawn; declined consent Baseline characteristics Intervention group (statins) Age, mean (SD): 53.2 (± 16.1) years Gender, M/F: 137/122 APACHE II, mean (SD): 19.4 (± 6.9) PaO₂/FiO₂, mean (SD): 123 (± 54.8) mmHg SOFA, mean (SD): 8.6 (± 3.2) Risk factor: direct ‐ smoke or toxic inhalation 1, aspiration of gastric contents 21, thoracic trauma 22, pneumonia 161; indirect ‐ sepsis 106, pancreatitis 5, non‐thoracic trauma 4; other 30 Control group (placebo) Age, mean (SD): 54.4 (± 16.7) years Gender, M/F: 170/110 APACHE II, mean (SD): 18.3 (± 6.2) PaO₂/FiO₂, mean (SD): 132.4 (± 55.4) mmHg SOFA, mean (SD): 9.0 (± 2.9) Risk factor: direct ‐ smoke or toxic inhalation 2, aspiration of gastric contents 29, thoracic trauma 10, pneumonia 154; indirect ‐ sepsis 118, pancreatitis 17, non‐thoracic trauma 8; other 36 Country: UK and Ireland Setting: multicentre; 40 ICUs
Interventions	Intervention group (statins) Participants: n = 259; 1 lost to follow‐up and excluded from analysis, treated = 254; analysed (ITT) = 258. Details: simvastatin; 80 mg, orally, once daily, for up to 28 days Additional details: in both groups, ICUs were encouraged to use lower tidal volumes (6 to 8 mL/kg of predicted bodyweight), plateau pressure < 30 cmH₂O (ARDS Network 2000) Control group (placebo) Participants: n = 281; 2 withdrew consent and were excluded from analysis, treated = 278; analysed (ITT) = 279 Details: identical tablet; for 28 days
Outcomes	Outcomes measured/reported: number of ventilator‐free days (up to day 28); change in oxygenation index and SOFA score; number of days free of non‐pulmonary organ failure; death from any cause (at 28 days); death before discharge from critical care or hospital; adverse events and serious adverse events related to the study drug Outcomes relevant to the review: mortality (at 28 days), ventilator‐free days up to day 28; adverse events (see note)
Notes	Funding/declarations of interest: UK Efficacy and Mechanisim Evaluation Programme, a Medical Research Council and NIHR partnership. 3 authors in receipt of funding from pharmaceutical manufacturer. "Funders had no role in the study design, data acquisition, data analysis, or manuscript preparation." Study dates: December 2010 to March 2014 Note: study authors report that "the most common reason for discontinuation of the study drug were discharge from critical care, death, and an adverse event that was considered to be related to the study drug". No additional details are provided in the study report and online supplementary appendix to indicate how many participants had study treatment discontinued because of an adverse event
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Sequence generation (selection bias)	Low risk	Randomization performed using automated, centralized 24‐hour service
Allocation concealment (selection bias)	Low risk	External randomization, in which allocation can be concealed
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: "Patients received once‐daily simvastatin (at a dose of 80 mg) or identical placebo tablets enterally for up to 28 days."
Blinding of outcome assessors for mortality (detection bias)	Low risk	No details. However, we did not expect blinding of outcome assessors to influence outcome data for mortality
Blinding of outcome assessors for other outcomes (detection bias)	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1 participant lost to follow‐up in intervention group, and 2 participants withdrew consent in control group. Data reported with different denominator figures not always consistent with these losses, but very small number and unlikely to influence results
Selective outcome reporting (reporting bias)	Unclear risk	Prospective trial registration ISRCTN88244364. Some outcomes not reported in full publication as stated in trial registration document, to include mortality at 12 months
Baseline characteristics	High risk	Differences apparent in ratio of PaO₂/FiO₂ (less in simvastatin group), reported by authors to be statistically significant
Other sources of bias	Low risk	No other sources of bias identified

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Early mortality	3	646	Risk Ratio (M‐H, Random, 95% CI)	1.14 [0.91, 1.42]
2 Ventilator‐free days up to day 28	3	646	Mean Difference (IV, Random, 95% CI)	‐2.20 [‐3.68, ‐0.71]
3 Adverse events	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

Methods	RCT Parallel group
Participants	Total number of randomized participants: 26 Inclusion criteria: 18 to 80 years of age; fulfils criteria of ARDS according to the AECC (Bernard 1994); ARDS diagnosis within 3 days of admission; fulfils CIRCI diagnosis according to Society of Critical Care Medicine of PLAs Guidelines 2006 Exclusion criteria: pregnant or breastfeeding; malignant disease; using immunosuppressing medications; history of bone marrow or lung transplant; history of primary or secondary adrenal disease; use of steroids in previous 3 months; rejects conventional treatment as stated in this study; took part in clinical trial in prior 30 days of this study Baseline characteristics Intervention group (corticosteroids) Age, mean (SD): 69.8 (± 14.9) years Gender, M/F: 9/3 APACHE II, mean (SD): 20.7 (± 6.4) SOFA, mean (SD): 9.4 (± 3.9) Risk factors: chest Infection 5; chest trauma 1; other internal organ injury 3; acute pancreatitis 1; mixed causes 2 Control group (placebo) Age, mean (SD): 55.9 (± 15.3) years Gender, M/F: 10/4 APACHE II, mean (SD): 21.4 (± 7.16) SOFA, mean (SD): 9.3 (± 2.1) Risk factors: chest Infection 6; chest trauma 1; other internal organ injury 4; acute pancreatitis 2; mixed causes 1 Country: China Setting: single‐centre
Interventions	Intervention group (corticosteroids) Participants: n = 12; losses = 0; analysed = 12 Details: stress dose glucocorticoid; hydrocortisone 100 mg IV 3 times a day for 7 days Additional details: lower tidal volume used Control group (placebo) Participants: n = 14; losses = 0; analysed = 14 Details: normal saline; 0.9% IV 100 mg 3 times a day for 7 days Additional details: lower tidal volume used
Outcomes	Outcomes measured/reported: APACHE II; SOFA; GCS (pre‐ and post‐treatment); number of ventilator‐free days (at day 28); number of coma‐free days (at day 28); number of coma events (at day 28); mortality (at day 28); length of ICU stay; arterial blood gas (pretreatment and 7 days after treatment) Outcomes relevant to the review: number of ventilator‐free days (at day 28); mortality (at day 28)
Notes	Funding/declarations of interest: Nanjing Technology Development Fund; Jiangsu Medical Development Learning Fund Study dates: June 2009 to December 2011 Note: study reported in Chinese. Data extraction and 'Risk of bias' assessment completed by Dr Henry HL Wu
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Sequence generation (selection bias)	Unclear risk	Described as randomized but no additional details
Allocation concealment (selection bias)	Unclear risk	No details
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	No details
Blinding of outcome assessors for mortality (detection bias)	Low risk	No details. However, we did not expect blinding of outcome assessors to influence outcome data for mortality
Blinding of outcome assessors for other outcomes (detection bias)	Unclear risk	No details
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No apparent losses
Selective outcome reporting (reporting bias)	Unclear risk	Clinical trials registration or pre‐published protocol not reported. Insufficient information to make judgement
Baseline characteristics	Low risk	Appear comparable
Other sources of bias	Low risk	No other source of bias identified

Study	Reason for exclusion
Abraham 1996	RCT, liposomal PGE₁ versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Abraham 1999	RCT, liposomal PGE₁ versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Annane 2006	Retrospective analysis of previous clinical trial of corticosteroids versus placebo. Retrospective analysis includes only participants with ARDS. Excluded because of ineligible study design
Anzueto 1996	RCT, Exosurf versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Ardizzoia 1993	RCT, PTX versus standard therapy. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Bastin 2010	RCT, NAC versus control, adults undergoing lung resection with open‐lung ventilation for lung cancer, but not specifically patients with ALI or ARDS
Bastin 2016	RCT, NAC versus control, adults undergoing lung resection with open‐lung ventilation, but not specifically patients with ALI or ARDS
Bernard 1987	RCT, corticosteroids (methylprednisolone) versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Bernard 1997	RCT, multi‐arm study. NAC; OTZ; control. Included in previous version of the review (Adhikari 2004).Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Bernard 1999	RCT, IL‐10 (use of control not described). Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Bone 1989	PGE₁ versus placebo. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Confalonieri 2005	RCT, hydrocortisone versus control. Inclusion criterion is for community‐acquired pneumonia rather than specifically ARDS.
Cornet 2014	RCT, participants with ARDS, recombinant human activated protein C versus saline. This drug is now withdrawn from the market and it is not feasible to include this study in the review
Domenighetti 1997	RCT, NAC versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Forel 2006	RCT, participants with ARDS. Trial of neuromuscular blocking agent for mechanical ventilation of patients, rather than treatment of ARDS
Gainnier 2004	RCT, participants with ARDS. Trial of neuromuscular blocking agent for mechanical ventilation of patients, rather than treatment of ARDS
Gottlieb 1994	RCT, neutrophil elastase inhibitor versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Gregory 1997	RCT, surfactant (at 2 doses) versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Holcroft 1986	RCT, PGE₁ versus control. Included in previous version of the Review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Hua 2013	RCT, participants with ARDS, terlipressin versus dopamine, but does not include a placebo or control as a comparison agent and therefore excluded
Jepsen 1992	RCT, NAC versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Liu 2008	RCT, participants with ALI, recombinant human activated protein C versus control. This drug is now withdrawn from the market and it is not feasible to include this study in the review
Markart 2007	Phase I/II pilot study of recombinant surfactant protein C‐based surfactant (venticute), study design not relevant for review, no relevant outcomes reported
Meduri 1998	RCT, corticosteroids (methylprednisolone) versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Papazian 2010	RCT, participants with ARDS. Trial of neuromuscular blocking agent for mechanical ventilation of patients, rather than treatment of ARDS
Presneill 2002	RCT, granulocyte‐macrophage colony‐stimulating factor versus placebo. Included in previous version of the review (Adhikari 2004). Excluded because ALI or ARDS is not a specific inclusion criteria.
Reines 1985	RCT, thromboxane synthase inhibitor (Dazoxiben) versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Reines 1992	RCT, surfactant versus placebo. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Rossignon 1990	RCT, PGE₁ versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Shoemaker 1986	RCT, PGE₁ versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Shyamsundar 2010	RCT, recombinant human keratinocyte growth factor versus control, but given to prevent not treat ALI and therefore excluded
Steinberg 1990	RCT, indomethacin versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Suter 1994	RCT, NAC versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Tuxen 1987	RCT, acyclovir versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Vincent 2009	RCT, inactivated recombinant factor VIIa versus control. Dose escalation study, not relevant for review without agreed appropriate dosing for this agent
Weg 1994	RCT, surfactant versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)
Weigelt 1985	RCT, methylprednisolone versus control. Included in previous version of the review (Adhikari 2004). Excluded because publication date was prior to 2000 (see Differences between protocol and review)

Methods	RCT
Participants	Target participant recruitment: 150 Inclusion criteria: suspected or proven infection; hypoxaemia: PaO₂/FiO₂ ≤ 300 mmHg; bilateral infiltrates consistent with pulmonary oedema; positive‐pressure mechanical ventilation through an endotracheal tube; no clinical evidence of left atrial hypertension to explain bilateral infiltrates; presence of ≥ 3 of the 4 SIRS criteria. If only 2 criteria are evidenced, 1 must be temperature or WBC Exclusion criteria: < 18 years of age; inability to obtain consent; patient, surrogate, or physician not committed to full support; moribund state in which death was perceived to be imminent; morbid obesity; malignancy or other irreversible disease or condition for which 6‐month mortality is estimated to be > 50%; known HIV‐positive with known end‐stage processes; prior cardiac arrest requiring CPR without fully demonstrated neurological recovery; or NYHA Class IV; pregnant or nursing; ALI/ARDS induced by mechanical or chemical injury directly to the lung (including burns, trauma, and near drowning); > 48 hours since all inclusion criteria are met; neuromuscular disease that impairs ability to ventilate without assistance; severe chronic respiratory disease, severe pulmonary hypertension, or ventilator dependency; chest wall deformity resulting in severe exercise restriction, secondary polycythaemia, or respirator‐dependent; history of organ transplant (including bone marrow); severe chronic liver disease, as determined by a Child‐Pugh Score > 10; haemoglobin persistently < 7.0 g/dL; platelet count < 50,000/mm³; prolonged INR > 3; bleeding disorders unless corrective surgery has been performed; active internal bleeding; major surgery within 24 hours before study drug infusion, or evidence of active bleeding postoperatively, or plan for any major surgery within 3 days after study drug infusion; diffuse alveolar haemorrhage from vasculitis; known bleeding diathesis; presence of an epidural catheter or lumbar puncture within 48 hours before study drug infusion or anticipation of receiving an epidural catheter or a lumbar puncture within 48 hours after study drug infusion; stroke within 3 months of study entry; trauma with an increased risk of life‐threatening bleeding; a history of severe head trauma that required hospitalization, or intracranial surgery within 2 months of study entry; any history of intracerebral arteriovenous malformation, cerebral aneurysm, or central nervous system mass lesion; uses of certain medications or treatment regimens such as chemotherapy, unfractionated heparin, low‐molecular‐weight heparin, warfarin, antithrombin III, acetylsalicylic acid, glycoprotein IIb/IIIa antagonists, thrombolytic therapy, and activated Protein C are restricted; participation in another experimental medication study within 30 days of study entry Country: USA Setting: multicentre; ICU
Interventions	Intervention group Participants: n = 75 Details: in the first part of this study, recombinant chimeric anti‐tissue factor antibody ALT‐836 was administered as a single dose (0.06 mg/Kg) through an intravenous infusion over 15 minutes. In the second part of this study, up to 4 doses (0.06 mg/kg) of ALT‐836 were administered through an intravenous infusion over 15 minutes Control group Participants: n = 75 Details: in the first part of this study, a single dose of placebo was administered through an intravenous infusion over 15 minutes. In the second part of this study, up to 4 doses of placebo were administered through an intravenous infusion over 15 minutes
Outcomes	Primary outcomes: safety profile of the study drug (throughout 28 days following treatment); number of ventilator‐free days (at day 28) Secondary outcomes: mortality (at day 7, 14, 21, 28 and 60); length of hospitalization (at day 28); length of ICU stay (at day 28); number of non‐pulmonary organ failure‐free days (at day 28); changes in physiological variables of lung injury (throughout the 28 days following treatment); changes in disease severity and lung injury scores (throughout the 28 days following treatment); effects of the study drug and the aetiology of the disease (at day 28); pharmacokinetics and pharmacodynamics (throughout the 28 days following treatment); immunogenicity (throughout the 28 days following treatment)
Notes	Funding/declarations of interest: Altor BioScience; National Heart, Lungs, and Blood Institute Study dates: April 2009 to January 2013 Note: study is completed but results are not published. We await publication of full report to assess eligibility

Methods	RCT
Participants	Target participant recruitment: 72 Inclusion criteria: presence of ARDS in the first 24 hours of diagnosis; PEEP > 5 cmH₂O; patients whose relatives give written consent to participate; between 18 and 75 years of age Exclusion criteria: pregnant women, breastfeeding or post partum; COPD; hypersensitivity to surfacen or other component of the formulation Country: Cuba Setting: ICU
Interventions	Intervention group Participants: n = not given Details: conventional treatment of oxygenation and mechanical ventilation plus surfacen 100 mg (4 mL) every 8 hours for 3 days Control group Participants: n = not given Details: conventional treatment of oxygenation and mechanical ventilation
Outcomes	Primary outcome: PaO₂/FiO₂ ratio (favourable when ≥ 200) (group A: 1 hour, 4 hours and 8 hours after each dose. Group B: 1 hour, 4 hours and 8 hours after haemodynamic stabilization) Secondary outcomes: gasometric evaluation (PaO₂, PaCO₂, pH); ventilatory evaluation; clinic evaluation; radiographic evaluation; mechanical ventilation days; total hospital days; condition of the participant; all‐cause mortality (at 28 days); adverse events (at 28 days)
Notes	Funding/declarations of interest: CENSA; MINSAP Study dates: March 2006

Trial name or title	A multi‐centre randomized, placebo controlled trial of nebulized heparin in participants with or at risk of developing Acute Respiratory Distress Syndrome, to determine if nebulized heparin improves long term physical function
Methods	RCT
Participants	Target participant recruitment: 256 Inclusion criteria: ≥ 18 years of age; receiving ventilation through an endotracheal tube; started ventilation yesterday or today; expected to require invasive ventilation for at least all of today and all of tomorrow; PaO₂ to FiO₂ ratio < 300; active ventilator circuit humidification Exclusion criteria: allergy to heparin; history of heparin‐induced thrombocytopenia; platelet count < 50 x 109/L; APTT prolonged to > 80 seconds, not due to anticoagulant therapy; uncontrolled bleeding; pulmonary bleeding during hospital admission; history of intracranial, spinal or epidural haemorrhage; neurosurgical procedures during hospital admission or such procedures planned; epidural catheter is in place; hepatic encephalopathy or history of gastrointestinal bleeding due to portal hypertension or biopsy proven cirrhosis with documented portal hypertension; tracheostomy in place; usually receives home oxygen; usually receives any type of assisted ventilation at home; cervical spinal cord injury associated with reduced long‐term ability to breathe independently; spinal or peripheral nerve disease with a likely prolonged reduction in the ability to breathe independently; receiving high‐frequency oscillation ventilation or extracorporeal membrane oxygenation; pregnant; treatment limits restrict the provision of renal replacement therapy, inotropes, vasopressors or prolonged invasive ventilation; usually treated with haemodialysis or peritoneal dialysis for end‐stage renal failure; dementia; death is deemed imminent or inevitable or there is underlying disease with a life expectancy of less than 90 days Country: Australia Setting: ICU
Interventions	Intervention group (nebulized liquid heparin) Participants: n = not given Details: 25,000 IU in 5 ml; study medication given every 6 hours for up to 10 days while the participant requires ventilation Control group (placebo) Participants: n = not given Details: 5 ml of nebulized liquid 0.9% sodium chloride; given every 6 hours for up to 10 days while the participant requires ventilation
Outcomes	Primary outcome: physical function assessed using the physical function component of the SF‐36 health survey Secondary outcomes: change in Murray Lung Injury Score assessed by review of medical records; change in plasma thrombin time, D‐Dimer, antithrombin thrombin levels and serum cytokines assessed by blood analysis; development of ALI or ARDS assessed by review of medical records; healthcare utilisation assessed by review of medical records; hospital stay duration; ICU stay duration; lung rescue therapies; major bleeding or other complications; mechanical VFDs; mortality; quality of life assessed by contact with participant or next of kin and undertaking EQ5D survey
Starting date	1 August 2012
Contact information	Email: barry.dixon@svhm.org.au
Notes	Funding/declarations of interest: St.Vincents Hospital/Institute

Trial name or title	Effect of nebulized budesonide on respiratory mechanics and oxygenation in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS)
Methods	RCT
Participants	Target participant recruitment: 60 Inclusion criteria: patients fulfilling the criteria of ALI/ARDS according to 2012 Berlin definition of ALI/ARDS Exclusion criteria: refusal of consent by relatives; < 18 or > 65 years of age; chronic obstructive pulmonary disease; restrictive respiratory insufficiency; increased intracranial pressure; bronchopleural fistula; acute myocardial infarction; neuromuscular disease Country: Egypt Setting: ICU
Interventions	Intervention group (budesonide) Participants: n = 30 Details: 1 mL to 2 mL budesonide suspension nebulized through endotracheal tube; regimen applied twice daily for 3 successive days; nebulization performed using specific ventilator nebulizer (pro‐Aeroneb professional nebulized system) with an oxygen flow of 8 L/min for 15 mins; before each session recruitment manoeuvre is done by increasing peak airway to ensure a plateau pressure of 30 cmH₂O for 30 seconds Control group (placebo) Participants: n = 30 Details: 2 mL isotonic saline is nebulized instead of budesonide
Outcomes	Primary outcome: PaO₂/FiO₂, calculated from the measured PaO₂ (from arterial blood gas analysis) and the inspired oxygen concentration. FiO₂ is the inspired fraction of oxygen given by anaesthesiologist whether pure oxygen (100% oxygen) or in combination with air (60% oxygen in 40% air) Secondary outcome: PIP; plateau pressure; both parameters are assessed from the screen of Binnette respirometer
Starting date	2014
Contact information	Email: dr.hatem_saber@hotmail.com
Notes	Funding/declarations of interest: South Valley University and Qena University Hospital

Trial name or title	Comparison of the efficacy and safety of FP‐1201‐lyo and placebo in the treatment of patients with moderate or severe acute respiratory distress syndrome: study protocol for a randomized controlled trial
Methods	RCT
Participants	Target participant recruitment: 300 Inclusion criteria: ≥ 18 years of age; trachea is intubated; receiving mechanical ventilation; diagnosis of moderate or severe ARDS according to the Berlin definition of ARDS; acute onset of respiratory failure within 1 week of a known clinical insult or new or worsening respiratory symptoms; respiratory failure associated with known ARDS risk factors and not fully explained by either cardiac failure or fluid overload; radiological abnormalities on chest X‐ray or on CT scan; radiological and hypoxaemia criteria must occur within the same 24‐hour period; time of onset of ARDS is defined as the time when the last of these 2 ARDS criteria is met; administration of the first dose of study drug planned to take place within 48 hours of moderate or severe ARDS diagnosis; signed written informed consent form from the participant or the participant’s personal legal representative or a professional legal representative Exclusion criteria: woman known to be pregnant or lactating; simultaneously taking part in another pharmacotherapy protocol; not expected to survive for 24 hours; has underlying clinical condition where, in the opinion of the investigator, it would be extremely unlikely that the patient would be able to come off ventilation; severe COPD requiring long‐term home oxygen therapy or mechanical ventilation except for CPAP or BIPAP used solely for sleep‐disordered breathing; congestive heart failure, defined as NYHA class IV; acute left ventricular failure; liver failure (Child‐Pugh grade C); received any prior IFN; known hypersensitivity to natural or recombinant IFN beta or to any of the excipients; receiving renal dialysis therapy for chronic renal failure; receiving extracorporeal membrane oxygenation, HFOV or any form of extracorporeal lung support; has had any form of mechanical ventilation (invasive or non‐invasive, excluding CPAP alone) for > 48 hours prior to the diagnosis of ARDS; noninvasive ventilation has to be continuously applied for at least 12 hours a day in these 48 hours; burns to ≥ 15% of their TBSA Country: 9 European countries Setting: multicentre; ICU
Interventions	Intervention group (FP‐1201‐lyo) Participants: n = 150 Details: FP‐1201‐lyo μg; administered intravenously as a bolus each day for 6 days Control group (placebo) Participants: n = 150 Details: placebo (powdered lyophilisate); administered intravenously as a bolus each day for 6 days
Outcomes	Primary outcomes: composite of death (at 28 days); days free of mechanical ventilation (at 28 days) Secondary outcomes: all‐cause mortality (at 28, 90, 180 and 360 days); days free of organ failure (at 28 days); length of hospital stay; efficacy, safety and exploratory variables
Starting date	28 December 2015
Contact information	Email: geoff.bellingan@uclh.nhs.uk
Notes	Funding/declarations of interest: Faron Pharmaceuticals Ltd.; European Union Seventh Framework Program; Mikael Maksimow, Markku Jalkanen and Ilse Piippo are employed by Faron Pharmaceuticals and hold Faron shares and/or options for shares. The other authors are members of the INTEREST trial Steering Committee and have received expenses only for participation in required study meetings

Trial name or title	Clinical study of rhGM‐CSF in the treatment of pulmonary extraneous acute respiratory distress syndrome
Methods	RCT
Participants	Target participant recruitment: 90 Inclusion criteria: between 18 and 70 years of age; the primary disease of ARDS is a non‐pulmonary sepsis, which is in line with the definition of sepsis in 2016; patient or family members agree to join the clinical study Exclusion criteria: pregnant women; patients with malignant tumour, immunodeficiency or autoimmune disease; white blood cell count is > 40 x 10⁹/L or the oxygenation index is less than 80; patient or family members need to withdraw from the study Country: China Setting: single‐centre; ICU
Interventions	Intervention group (thymosin) Participants: n = 30 Details: thymosin 20 mg intramuscular injection once a day for 7 days Intervention group (GM‐CSF) Participants: n = 30 Details: rhGM‐CSF 250 μg/m² intravenous injection once a day for 7 days Control group (standard therapy) Participants: n = 30 Details: conventional therapy
Outcomes	Primary outcomes: oxygenation index; HLA‐D expression rate of CD14 positive mononuclear cells Secondary outcomes: concentration of HMGB‐1, TNF‐a, PCT and GM‐CSF in plasma; concentration of HMGB‐1, TNF‐a and GM‐CSF in bronchoalveolar lavage fluid; APACHE II score, SOFA score, and lung injury score; duration of ventilator use, incidence of ventilator‐associated pneumonia; mortality (at 28 days)
Starting date	2 January 2018
Contact information	Email: phoenix413@163.com
Notes

Trial name or title	Human umbilical cord derived mesenchymal stem cells therapy in acute respiratory distress syndrome: a pilot study
Methods	RCT
Participants	Target participant recruitment: 12 Inclusion criteria: invasive ventilation, OI PaO₂/FiO₂ < 200; PEEP = 8 cmH₂O; bilateral infiltration of lung in X‐ray or CT; in first week after onset; still OI < 200 after protective ventilation or conservative fluid management Exclusion criteria: any malignant disease; cardiogenic pulmonary oedema; > 50% atelectasis either lung lobe in X‐ray; pregnancy or perinatal or lactation; previous end‐stage respiratory disease; > 3 organs failure; liver failure with MELD score > 40; stage III or IV pulmonary hypertension; noninvasive arterial and central venous catheter; concurrent deep venous thrombus or pulmonary embolism in 3 months; cerebral hernia; > 96 hours after ARDS onset; < 18 years of age Country: China Setting: single‐centre; University Hospital
Interventions	Intervention group (MSC) Participants: n = 6 Details: hucMSCs 10⁶/kg + NS 100 ml, IV drip Control group (placebo) Participants: n = 6 Details: normal saline 100 ml, IV drip
Outcomes	Primary outcome: safety Secondary outcomes: ventilator‐free days; oxygenation index change
Starting date	27 February 2018
Contact information	Email: haijinlv@163.com
Notes

PERMALINK

Pharmacological agents for adults with acute respiratory distress syndrome

Sharon R Lewis

Michael W Pritchard

Carmel M Thomas

Andrew F Smith

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings' tables and GRADE

Summary of findings for the main comparison. Corticosteroids compared to control for adults with acute lung injury and acute respiratory distress syndrome.

Summary of findings 2. Surfactants compared to control for adults with acute lung injury and acute respiratory distress syndrome.

Summary of findings 3. N‐acetylcysteine compared to control for adults with acute lung injury and acute respiratory distress syndrome.

Summary of findings 4. Statins compared to control for adults with acute lung injury and acute respiratory distress syndrome.

Summary of findings 5. Beta‐agonist compared to control for adults with acute lung injury and acute respiratory distress syndrome.

Results

Description of studies

Results of the search

1.

Included studies

Study population

Study setting

Interventions and comparisons

Outcomes

Funding sources

Early stopping

Excluded studies

Studies awaiting classification

Ongoing studies

Risk of bias in included studies

2.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Baseline characteristics

Other potential sources of bias

Effects of interventions

Corticosteroids versus control

Primary outcome

Early all‐cause mortality

1.1. Analysis.

Secondary outcomes

Late all‐cause mortality

Trial name or title	A comparative, randomized controlled trial for evaluating the efficacy of dexamethasone administration in the treatment of patients with the Acute Respiratory Distress Syndrome
Methods	RCT
Participants	Target participant recruitment: not given Inclusion criteria: ≥ 18 years of age; have acute onset of ARDS, as defined by the AECC criteria for ARDS (Bernard 1994); intubated and mechanically ventilated; provided signed written informed consent from the patient or the patient's personal legal representative Exclusion criteria: woman known to be pregnant or lactating; participating in another experimental treatment protocol; brain death; terminal‐stage cancer or other terminal disease; do‐not‐resuscitate orders; immune‐compromised; receiving corticosteroids or immunosuppressive drugs; > 24 hours elapsed after initially meeting the AECC ARDS criteria (Bernard 1994) before consent and results of initial standard ventilator settings could be obtained; severe COPD; congestive heart failure Country: Spain Setting: ICU
Interventions	Intervention group (dexamethasone) Participants: n = not given Details: dexamethasone; solution for injection Control group (standard treatment) Participants: n = not given Details: normal treatment but without dexamethasone
Outcomes	Primary outcomes: VFDs (at day 28) Secondary outcomes: all‐cause mortality (at Day 60); days on mechanical ventilation; number of extra‐pulmonary organ failures (at day 60)
Starting date	21 November 2012
Contact information	Email: osalidia.fernandez@gmail.com
Notes	Funding/declarations of interest: Fundación Mutua Madrileña

Trial name or title	A phase 3 clinical study to evaluate the efficacy and safety of intravenous MR11A8 in the treatment of patients with moderate or severe acute respiratory distress syndrome
Methods	RCT
Participants	Target participant recruitment: 120 Inclusion criteria: ≥ 20 years of age; Japanese patient with a diagnosis of moderate or severe ARDS according to the Berlin definition of ARDS; acute onset of respiratory failure within 1 week of a known clinical insult or new or worsening respiratory symptoms; respiratory failure associated with known ARDS risk factors and not fully explained by either cardiac failure or fluid overload; radiological abnormalities on chest X‐ray or on computerized tomography scan; hypoxaemia; moderate ARDS 100 mmHg = 5 cmH₂O; severe ARDS PaO₂/FiO₂ ≤ 100 mmHg with PEEP ≥ 5 cmH₂O; the radiological and hypoxaemia criteria in ARDS criteria must be met within the same 24‐hour period. The time of onset of ARDS is when the last of the 2 specified ARDS criteria is met; administration of the first dose of study drug must be planned to take place within 48 hours of first fulfilling the above inclusion criteria; patient is intubated and mechanically ventilated; signed informed consent form from the patient or the patient's personal legal representative or a professional legal representative Exclusion criteria: woman known to be pregnant, lactating or with a positive or indeterminate pregnancy test; patient is simultaneously taking part in another pharmacotherapy protocol; not expected to survive for 24 hours; has an underlying clinical condition where, in the opinion of the Investigator, it would be extremely unlikely that the patient would come off ventilation; severe chronic obstructive pulmonary disease requiring long‐term home oxygen therapy or mechanical ventilation (non‐invasive ventilation or tracheotomy) except for CPAP or BIPAP used solely for sleep‐disordered breathing; has congestive heart failure, defined as NYHA class 4; acute left ventricular failure; liver failure (Child‐Pugh grade C); received any prior IFN; known hypersensitivity to natural or recombinant IFN beta or to any of the excipients; receiving renal dialysis therapy for chronic renal failure; receiving extra‐corporeal membrane oxygenation, high‐frequency oscillatory ventilation or any form of extracorporeal lung support; had any form of mechanical ventilation (invasive or non‐invasive, excluding CPAP alone) for > 48 hours prior to the diagnosis of ARDS. Non‐invasive ventilation has to be continuously applied for ≥ 12 hours a day in these 48 hours; burns to ≥ 15% of their TBSA; receiving Sho‐saiko‐to or is scheduled to receive Sho‐saiko‐to during the study drug administration period Country: Japan Setting: multicentre; ICUs
Interventions	Intervention group (MR11A8) Participants: n = not given Details: MR11A8; 10 mcg; administered intravenously once daily for 6 days Control group (placebo) Participants: n = not given Details: placebo; same as intervention group
Outcomes	Primary outcome: all‐cause mortality (at day 28) Secondary outcomes: composite endpoint including any‐cause death (at day 28); days free of mechanical ventilation (within 28 days); all‐cause mortality (at day 90); mortality in ICU (up to day 28); mortality in hospital (up to day 28)
Starting date	16 July 2016
Contact information	Name: Maruishi Pharmaceutical Co., Ltd, Clinical Development Department, Pharmaceutical Research and Development Division
Notes	Funding/declarations of interest: Maruishi Pharmaceutical Co., Ltd.

Trial name or title	ASpirin as a Treatment for ARDS (STAR): a phase 2 randomized control trial
Methods	RCT
Participants	Target participant recruitment: 60 Inclusion criteria: ≥ 16 years of age; receiving invasive mechanical ventilation; ARDS as defined by the Berlin definition Exclusion criteria: > 72 hours from the onset of ARDS; < 16 years of age; pregnant; participation in a clinical trial of an investigational medicinal product within 30 days; current treatment with aspirin or within the past 4 weeks; platelet count < 50 x 10⁹/L; haemophilia or other haemorrhagic disorder or concurrent therapeutic anticoagulant therapy; history of aspirin‐sensitive asthma or nasal polyps associated with asthma; active or history of recurrent peptic ulcer and/or gastric/intestinal haemorrhage or other kinds of bleeding such as cerebrovascular haemorrhage; traumatic brain injury; active gout; currently receiving methotrexate; severe chronic liver disease with Child‐Pugh score > 12; known hypersensitivity or previous adverse reaction to salicylic acid compounds or prostaglandin synthetase inhibitors; physician decision that aspirin is required for proven indication; contraindication to enteral drug administration; treatment withdrawal imminent within 24 hours; consent declined Country: UK Setting: ICU
Interventions	Intervention Group (aspirin) Participants: n = not given Details: aspirin; 75 mg enterally once daily for a maximum of 14 days Control group (placebo) Participants: n = not given Details: lactose powder placebo enterally once daily for a maximum of 14 days
Outcomes	Primary outcome: OI (at day 7) Secondary outcomes: OI (at days 4 and 14); SOFA score (at days 4, 7 and 14); Crs (at days 4, 7 and 14); P/F ratio (at days 4, 7 and 14); safety and tolerability as assessed by the occurrence of serious adverse events and suspected unexpected serious adverse reactions (up to 28 days after completion of study drug)
Starting date	January 2015
Contact information	Professor Danny F McAuley
Notes	Funding/declarations of interest: Belfast Health and Social Care Trust; Queen's University, Belfast; Northern Ireland Clinical Trials Unit

Trial name or title	GM‐CSF Inhalation to Improve Host Defense and Pulmonary Barrier Restoration (GI‐HOPE). A Randomized, Double‐blind, Parallel Group, Multicenter, Phase II Study
Methods	RCT
Participants	Target participant recruitment: 45 Inclusion criteria: signed informed consent form by the patient or a legal representative; between 18 and 75 years of age; women who have been post‐menopausal for > 1 year or women of childbearing potential period using a highly efficient method of contraception (i.e. a method with < 1% failure rate such as combined hormonal contraception, progesterone‐only hormonal contraception; diagnosis of pneumonia‐associated ARDS, where the underlying condition is CAP or HAP in patients not on invasive ventilation upon diagnosis of HAP; diagnosis of ARDS according to the Berlin ARDS definition; requirement for positive pressure ventilation (non‐invasive or endotracheal tube) for > 72 hours in total with inspiratory oxygen concentration (FiO₂) ≥ 50% (or less when on additional ECMO therapy) not > 14 days Exclusion criteria: receiving vasopressors of > 100 µg/min; history of liver cirrhosis Child Pugh C, chronic haemodialysis (before severe pneumonia/ARDS), lung cancer; malignancy with expected survival time of < 6 months; history of or listing for lung transplantation; highly immunosuppressive therapy or anti‐malignant combination chemotherapy within 3 weeks prior to first dose of study drug; any anti‐malignant chemotherapy within 24 hours prior to first dose of study drug; AIDS or known history of HIV infection; pregnancy; autoimmune thrombocytopenia, myelodysplastic syndromes with > 20% marrow blast cells; history or presence of hypersensitivity or idiosyncratic reaction to molgramostim or to related compounds; participation in another clinical trial within 90 days prior to the first dose of study drug Country: Germany Setting: multicentre; ICU
Interventions	Intervention group (rhGM‐CSF; 150 mcg) Participants: n = 15 Details: once daily inhaled rhGM‐CSF for 3 days Intervention group (rhGM‐CSF; 450 mcg) Participants: n = 15 Details: same as other group Control group (placebo) Participants: n = 15 Details: inhaled placebo; same as other group
Outcomes	Primary outcome: GI‐HOPE score representing changes at day 4/5 with respect to baseline (at baseline and day 4 and 5) Secondary outcomes: number of participants with adverse events, serious adverse events and adverse drug reactions (at baseline to 28 days); oxygenation (at baseline to day 11); APACHE (at baseline to day 11); SOFA (at baseline to day 11); extravascular lung water index (at baseline to day 11); C‐reactive Protein (at baseline to day 11); days on vasoactive drugs (at baseline to day 28); all‐cause mortality (at baseline to day 28); serum GM‐CSF (at baseline and days 1 to 4)
Starting date	January 2016
Contact information	Email: susanne.herold@innere.med.uni‐giessen.de
Notes	Funding/declarations of interest: University of Giessen

Trial name or title	A phase 1/2 study to assess the safety and efficacy of MultiStem® therapy in subjects with acute respiratory distress syndrome
Methods	RCT
Participants	Target participant recruitment: 36 Inclusion criteria: between 18 and 90 years of age; moderate to severe ARDS, as defined by the Berlin definition, requiring an endotracheal or tracheal tube; able to receive investigational medicinal product within 96 hours of meeting the last of the ARDS diagnosis criteria Exclusion criteria: concurrent illness that shortens life expectancy to < 6 months; other serious medical or psychiatric illness Country: USA and UK Setting: ICU
Interventions	Intervention group (low dose MultiStem) Participants: n = not given Details: not given Intervention group (high dose MultiStem) Participants: n = not given Details: not given Control group Participants: n = not given Details: highest safe MultiStem dose (from cohorts 1 and 2) or placebo
Outcomes	Primary outcomes: frequency of sustained hypoxaemia or hypotension (within 4 hours); SUSARs (within 24 hours) Secondary outcomes: frequency of adverse events (up to 365 days); changes in vital signs (up to 7 days); changes in blood safety laboratories (up to 7 days); VFDs (28 days); ICU‐free days (28 days); total length of hospital stay (28 days); all‐cause mortality (28 days); changes in levels of oxygenation (up to 28 days); changes in PEEP (up to 28 days); changes in respiratory physiologic measures including lung compliance and airway resistance (peak and plateau pressures) (up to day 365); all‐cause mortality (up to day 365)
Starting date	January 2016
Contact information	Email: ating@athersysltd.co.uk
Notes	Funding/declarations of interest: Athersys Inc; Athersys Limited; Cell Therapy Catapult

Trial name or title	A randomized, blind, placebo‐controlled, parallel group, multicenter study to evaluate the safety and dose response relationship of ulinastatin for acute respiratory distress syndrome (ARDS)
Methods	RCT
Participants	Target participant recruitment: 60 Inclusion criteria: provided signed written informed consent form from the patient or the patient's legal representative; men or women ≥ 18 years of age; ARDS defined using 2012 Berlin Criteria; ARDS diagnosed ≤ 7 days; mechanically ventilated (invasive or noninvasive or both); 100 mmHg < PaO₂/FiO₂ < 250 mmhg with CPAP/PEEP ≥ 5 cmH₂O Exclusion criteria: patients with known hypersensitivity to ulinastatin/adjuvant or patient with allergic constitution; with artificial organ replacement therapy for liver or kidney; GCS ≤ 8; cardiogenic pulmonary oedema as the only or primary reason for respiratory failure; ARDS caused by burning, drowning, poisoning; presence of severe chronic liver diseases (Child‐Pugh score 12 ‐ 15) or severe chronic respiratory disease with a PaCO₂ > 50 mmHg or the use of home oxygen; neutrophils < 1.5 × 10⁹/L; moribund patients, or with recent cardiopulmonary arrest; needing long‐term glucocorticoid treatment or need to be treated with immunosuppressive drugs; no intent/unwillingness to follow lung protective ventilation strategy or fluid management protocol; lung transplant; with malignancy, expected to live no longer than 6 months; pregnant or breastfeeding; have participated in any clinical study within 3 months prior to the screening; with any condition that in the opinion of the investigator would add to the patient's risk or jeopardize the operation of the study Country: China Setting: ICU
Interventions	Intervention group (Ulinastatin; 4.8 million units per day) Participants: n = 15 Details: will receive study drug for 7 to 14 days Intervention group (Ulinastatin; 2.4 million units per day) Participants: n = 15 Details: same as previous intervention Intervention group (Ulinastatin; 1.2 million units per day) Participants: n = 15 Details: same as previous intervention Control group Participants: n = 15 Details: same as intervention groups using control agent
Outcomes	Primary outcome: incidence of adverse events (day 1 to 90) Secondary outcomes: changes of PaO₂/FiO₂ ratio (day 0 and 1 to within 24 hours after last treatment); days alive and off ventilator (day 1 to 28); days in the ICU (day 1 to 14); changes of pulmonary compliance (day 1, 3, 7, and within 24 hours after last treatment); rate of new organ failure (day 1 to 90); changes of APACHE Ⅱ score from baseline (day 3 ,7 and within 24 hours after last treatment); changes of Murray Lung Injury Score from baseline (day 3 ,7 and within 24 hours after last treatment); changes of SOFA score from baseline (day 3 ,7 and within 24 hours after last treatment); all‐cause mortality (day 28 ,90 and day 1 to 14)
Starting date	August 2016
Contact information	Name: Dr Yimin Li
Notes	Funding/declarations of interest: First Affiliated Hospital of Guangzhou Medical University

Trial name or title	A phase 2, randomized, double‐blind, placebo‐controlled, preliminary efficacy study of IC14 in acute respiratory distress syndrome
Methods	RCT
Participants	Target participant recruitment: 160 Inclusion criteria: ICU admission; between 18 and 70 years of age; presence of a known ARDS clinical risk within 7 days of onset; anticipated duration of mechanical ventilation > 48 hours Exclusion criteria: treatment with a drug or device within the last 30 days that has not received regulatory approval at the time of study entry; intubation for cardiopulmonary arrest; DNAR status; intubation for status asthmaticus, pulmonary embolus, myocardial infarction; anticipated survival < 48 hours from intubation; anticipated survival < 28 days due to pre‐existing medical condition; significant pre‐existing organ dysfunction; currently receiving home oxygen therapy as documented in medical record; pre‐existing congestive heart failure; chronic renal failure requiring renal replacement therapy; severe chronic liver disease; organ transplant recipient; chronic high‐dose corticosteroids; oncolytic drug therapy within the past 14 days; known HIV positive; current treatment with enbrel (etanercept), remicade (infliximab), humira (adalimumab), cimzia (certolizumab), or simponi (golimumab), kineret (anakinra), or arcalyst (rilonacept); pregnancy; history of hypersensitivity or idiosyncratic reaction to IC14; deprivation of freedom by administrative or court order Country: USA Setting: ICU
Interventions	Intervention group (IC14) Participants: n = not given Details: 4 mg/kg on study day 1, then 2 mg/kg once daily on study days 2 to 4 Control group (placebo) Participants: n = not given Details: normal saline for 4 days beginning within 48 hours of meeting inclusion criteria
Outcomes	Primary outcomes: safety (28 days); VFDs (28 days) Secondary outcomes: change in ARDS biologic markers (28 days)
Starting date	11 January 2017
Contact information	Email: garry.redlich@implicitbioscience.com
Notes	Funding/declarations of interest: Implicit Bioscience

Trial name or title	Repair of acute respiratory distress syndrome by stromal cell administration (REALIST): an open label dose escalation phase 1 trial followed by a randomized, double‐blind, placebo‐controlled phase 2 trial
Methods	RCT
Participants	Target participant recruitment: 75 Inclusion criteria: ≥ 16 years of age; ARDS as defined by the Berlin definition; onset within 1 week of identified insult; within the same 24 hours time period; hypoxic respiratory failure (PaO₂/ FiO₂ ratio ≤ 27 kPa on PEEP ≥ 5 cmH₂O); bilateral infiltrates on chest X‐ray consistent with pulmonary oedema not explained by another pulmonary pathology; respiratory failure not fully explained by cardiac failure or fluid overload; receiving invasive mechanical ventilation Exclusion criteria: > 48 hours from the onset of ARDS; < 16 years of age; pregnant; participation in clinical trial of an investigational medicinal product within 30 days; major trauma in the prior 5 days; presence of any active malignancy (other than non‐melanoma skin cancer) that required treatment within the last year; WHO Class III or IV pulmonary hypertension; venous thromboembolism currently receiving anticoagulation or within the past 3 months; currently receiving ECLS; severe chronic liver disease with Child‐Pugh score > 12; DNAR order in place; treatment withdrawal imminent within 24 hours; consent declined; prisoners; non‐English‐speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; previously enrolled in the REALIST trial Country: UK Setting: ICU
Interventions	Intervention group (MSC) Participants: n = not given Details: human umbilical cord‐derived CD362 enriched MSCs; maximum tolerated dose from the phase 1 trial will be infused over 30 to 90 minutes Control group (placebo) Participants: n = not given Details: Plasma‐Lyte 148 infused over 30 to 90 minutes
Outcomes	Primary outcomes: OI (at day 7); incidence of serious adverse events (at 28 days) Secondary outcomes: OI (days 4 and 14); SOFA score (days 4, 7 and 14); Crs (days 4, 7 and 14); P/F ratio (days 4, 7 and 14)
Starting date	22 November 2018
Contact information	Email: d.f.mcauley@qub.ac.uk
Notes	Funding/declarations of interest: Belfast Health and Social Care Trust; Queen's University, Belfast; Northern Ireland Clinical Trials Unit; NHS Blood and Transplant

Trial name or title	A phase IIa, placebo controlled, multicenter pilot study to evaluate the safety and efficacy of BIO‐11006 inhalation solution in patients with acute respiratory distress syndrome
Methods	RCT
Participants	Target participant recruitment: 60 Inclusion criteria: patients between 18 and 75 years of age; provided (or relative has) written informed consent and authorisation for use and disclosure of protected health information; has a clinical diagnosis of sepsis or septic shock; enrolment must occur within 48 hours of first meeting ARDS criteria according to the Berlin definition of ARDS (ARDS Definition Task Force 2012) and no more than 72 hours from the initiation of mechanical ventilation Exclusion criteria: < 18 or > 75 years of age; > 48 hours since first meeting ARDS criteria according to the Berlin definition of ARDS; pregnant or breastfeeding; prisoner; any other irreversible disease or condition for which 6‐month mortality is estimated to be > 50%; moderate to severe liver failure (Child Pugh Score > 12); severe chronic respiratory disease with a PaCO₂ > 50 mmHg or the use of home oxygen; patient, surrogate, or physician not committed to full support; major trauma in the prior 5 days; lung transplant patient; no consent/inability to obtain consent; moribund patient not expected to survive 24 hours; WHO Functional; class III or IV pulmonary hypertension; no intent/unwillingness to follow lung protective ventilation strategy or fluid management protocol; currently receiving extracorporeal life support or high‐frequency oscillatory ventilation; known hypersensitivity to BIO 11006; burn victims > 20% TBSA or with known airway inhalation injury Country: USA Setting: multicentre; ICU
Interventions	Intervention group (BIO‐11006) Participants: n = 30 Details: aerosolized BIO‐11006; 125 mg in 3 mL half normal saline; twice daily plus ventilation for up to 28 days Control group (placebo) Participants: n = 30 Details: aerosolized placebo; 3 mL half normal saline; twice daily plus ventilation for up to 28 days
Outcomes	Primary outcome: incidence of treatment‐emergent adverse events (at 28 days) Secondary outcomes: mortality (at 28 days and 180 days); number of ICU‐free days (at 28 days); VFDs (at 28 days); change in S/F ratio (at 28 days); change in pro‐inflammatory biomarkers from baseline to end of treatment (pretreatment and end of treatment period)
Starting date	5 August 2017
Contact information	Email: bdickson@biomarck.com
Notes	Funding/declarations of interest: BioMarck Pharmaceuticals, Ltd.

Trial name or title	NAC in early acute respiratory distress syndrome
Methods	RCT
Participants	Target participant recruitment: 52 Inclusion criteria: adult patients admitted to the medical intensive care unit or coronary care unit; mechanically ventilated with a positive end expiratory pressure > 5 cmH₂O, with noncardiogenic pulmonary oedema on chest x‐ray within 48 hours of being noted to have a P/F ratio < 150 Exclusion criteria: patients < 18 years of age; patients for whom no aggressive measures are desired; already receiving "rescue methods" (prone positioning, advanced ventilator modes, paralytics); trauma patients; vulnerable patient groups (pregnant, prisoners); have undergone a surgical operation during their time on the ventilator; with end‐stage liver disease; on chronic ventilators; asthmatics Country: USA Setting: ICU
Interventions	Intervention group (NAC) Participants: n = not given Details: not given Control group Participants: n = not given Details: not given
Outcomes	Primary outcome: ventilator days (from time of intubation until one of predefined endpoints (up to 60 days)) Secondary outcome: ICU days (from time of admission to the ICU until transfer out of the unit (up to 60 days)); mortality (up to 60 days); P/F ratio (daily until predefined endpoints (up to 60 days)); use of "rescue" manoeuvre (daily until the predefined endpoints (up to 60 days))
Starting date	1 February 2018
Contact information	Email: drjudlewis@gmail.com
Notes