Guideline Management ARDS

Guidelines
BMJ Open Resp Res: first published as 10.1136/bmjresp-2019-000420 on 24 May 2019. Downloaded from http://bmjopenrespres.bmj.com/ on November 20, 2019 by guest. Protected by
Guidelines on the management of acute
respiratory distress syndrome
Mark J D Griffiths,‍ ‍ 1 Danny Francis McAuley,2 Gavin D Perkins,3 Nicholas Barrett,4
Bronagh Blackwood,2 Andrew Boyle,2 Nigel Chee,5 Bronwen Connolly,6 Paul Dark,7
Simon Finney,‍ ‍ 1 Aemun Salam,1 Jonathan Silversides,2 Nick Tarmey,5
Matt P Wise,8 Simon V Baudouin9
To cite: Griffiths MJD, Abstract required of carers for these complex patients.

McAuley DF, Perkins GD, et al. The Faculty of Intensive Care Medicine and Intensive Care Indeed, the current state of the art for the
Guidelines on the management Society Guideline Development Group have used GRADE management of ARDS has been recently
of acute respiratory distress methodology to make the following recommendations for
syndrome. BMJ Open Resp Res reviewed1–4 and comparable guidelines have
the management of adult patients with acute respiratory been produced by national and international
2019;6:e000420. doi:10.1136/
distress syndrome (ARDS). The British Thoracic Society
bmjresp-2019-000420 stakeholders.5 6
supports the recommendations in this guideline.
Where mechanical ventilation is required, the use of
Received 7 March 2019
low tidal volumes (<6 ml/kg ideal body weight) and
Revised 1 April 2019 Scope
airway pressures (plateau pressure <30 cmH2O) was
recommended. For patients with moderate/severe ARDS The topics considered were chosen by the
(PF ratio<20 kPa), prone positioning was recommended Guideline Development Group (GDG) in the
for at least 12 hours per day. By contrast, high frequency light of results from a survey carried out for
oscillation was not recommended and it was suggested the Intensive Care Society (ICS), including
that inhaled nitric oxide is not used. The use of a 556 responses from 3200 members. Popular
conservative fluid management strategy was suggested
topics were excluded by the GDG if it was felt
copyright.
for all patients, whereas mechanical ventilation with
that there was a dearth of evidence (eg, appro-
high positive end-expiratory pressure and the use of the
neuromuscular blocking agent cisatracurium for 48 hours priate diagnostic investigations and the role
was suggested for patients with ARDS with ratio of arterial of specialist centres), when the evidence was
oxygen partial pressure to fractional inspired oxygen (PF) not specific to ARDS (weaning from mechan-
ratios less than or equal to 27 and 20 kPa, respectively. ical ventilation, nutrition and the timing of
Extracorporeal membrane oxygenation was suggested as tracheostomy) and if there was overlap with
an adjunct to protective mechanical ventilation for patients existing guidelines (post-ICU (intensive care
with very severe ARDS. In the absence of adequate unit) care and rehabilitation).
evidence, research recommendations were made for the
use of corticosteroids and extracorporeal carbon dioxide
removal.
Definitions
ARDS was first reported in a case series from
Denver in 1967.7 The American European
Introduction Consensus Conference (AECC) 1994 defined
Aims ARDS as ‘an acute inflammatory syndrome mani-
The purpose of this guideline is to provide an festing as diffuse pulmonary oedema and respira-
evidence-based framework for the manage- tory failure that cannot be explained by, but may
ment of adult patients with acute respiratory co-exist with, left-sided heart failure’.8 In 2012, the
distress syndrome (ARDS) that will inform AECC definition was re-evaluated and minor
© Author(s) (or their both key decisions in the care of individual alterations were proposed by the European
employer(s)) 2019. Re-use patients and broader policy. Our recommen- Society of Intensive Care Medicine ARDS Defi-
permitted under CC BY-NC. No dations are neither dictates nor standards of nition Task Force. This iteration recognised 3
commercial re-use. See rights
and permissions. Published by care. We cannot take into account all of the grades of severity depending on the degree
BMJ. features of individual patients and complex of hypoxaemia and stipulated the application
For numbered affiliations see local factors; all we can do is to synthesise rele- of at least 5 cmH2O of positive end-expira-
end of article. vant evidence and to put it into the context tory pressure (PEEP) or continuous positive
of current critical care medicine. Similarly, airway pressure. This so-called Berlin defini-
Correspondence to
Professor Mark J D Griffiths; our recommendations are not comprehen- tion was validated using retrospective cohorts
mark.griffiths@bartshealth. sive: these guidelines have relevance to a frac- and captures patients with a mortality of 24%
nhs.uk tion of the total number of decisions that are in patients with mild ARDS, rising to 48% in
Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

1
Open access
the group of patients with the most severe respiratory admitted to an ICU suggesting that LUNG SAFE may
failure.9 have underestimated both ARDS incidence and over-
A four-point lung injury scoring system (Murray Score looked diagnoses.14
or LIS) is the most widely used means of quantifying Survivors commonly suffer from muscle weakness and
ARDS severity. It is based on the level of PEEP, the ratio neuropsychiatric problems, such that fewer than 50%
of the partial pressure of arterial oxygen (PaO2) to the have returned to work 12 months after leaving intensive
fraction of inspired oxygen (FiO2), the dynamic lung care.15 However, it is unusual for ARDS survivors to be
compliance and the degree of radiographic infiltration.7 significantly limited by chronic respiratory failure. There-
Although the LIS has been widely used in clinical studies fore, ARDS is important both clinically and financially,
and a score of >3.0 is commonly used as a qualifying because it is a not uncommon contributor to the deaths
threshold for support with extracorporeal membrane of critically ill patients of all ages and because survivors
oxygenation (ECMO), it cannot predict outcome during carry on suffering from the sequelae of critical illness
the first 24–72 hours of ARDS.8 When the scoring system long after they leave hospital.16
is used 4–7 days after the onset of the syndrome, scores of
2.5 or higher predicted a complicated course requiring
prolonged mechanical ventilation.9 Pathophysiology
As a syndrome rather than a disease, there is no labo- The pathophysiology of ARDS results from acute inflam-
ratory, imaging or other ‘gold standard’ diagnostic inves- mation affecting the lung’s gas exchange surface, the
tigation for ARDS. Therefore like acute kidney injury alveolar-capillary membrane.1 Increased permeability of
(AKI), ARDS is caused by a huge range of conditions and the membrane associated with the recruitment of neutro-
as a consequence patients with ARDS are heterogeneous. phils and other mediators of acute inflammation into
The outcome of these patients is determined by the the airspace manifests as high permeability pulmonary
underlying causes of ARDS, patient-specific factors such oedema. The resulting acute inflammatory exudate inac-
as comorbidities, clinical management and the severity tivates surfactant leading to collapse and consolidation
of illness. of distal airspaces with progressive loss of the lung’s gas
exchange surface area. This would be compensated for
by hypoxic pulmonary vasoconstriction, if the inflamma-
Epidemiology and outcomes tory process did not also effectively paralyse the lung’s
copyright.
Using the AECC definition, several population-based means of controlling vascular tone, thereby allowing
studies of ARDS showed a fairly consistent picture of deoxygenated blood to cross unventilated lung units on
the age, mortality and severity of illness; however, there its way to the left heart. The combination of these two
was almost a fourfold difference in incidence, probably processes causes profound hypoxaemia and eventually
contributed to by differences in study design and ICU type 2 respiratory failure as hyperventilation fails to keep
utilisation.10 In the USA, there are estimated to be 190 000 pace with carbon dioxide production.
cases and 74 000 deaths annually from ARDS.11 Whereas
in a third world setting, from 1046 patients admitted to a Diagnosis
Rwandan hospital over 6 weeks, 4% (median age 37 years) Any diagnostic strategy for ARDS is sufficiently dependent
met modified ARDS criteria. Only 30.9% of patients with on local factors, such as the prevalent causes of infec-
ARDS were admitted to an ICU, and hospital mortality tious pneumonia and access to imaging modalities, that
was 50.0%. This study used the Kigali modification of a single protocol cannot be recommended. An exem-
the Berlin definition: without a requirement for PEEP, plar from a tertiary referral centre used to dealing with
hypoxia threshold of SpO2/FiO2 less than or equal to complex and very severe cases is included (figure 1, p43–
315, and bilateral opacities on lung ultrasound or chest 44). There are two main broad categories of condition
radiograph.12 that resemble ARDS but have a distinct pathophysiology:
The recently published LUNG SAFE trial was designed first, cardiovascular conditions of rapid onset including
to study prospectively the performance of the Berlin defi- left heart failure, right-to-left vascular shunts usually with
nition and to reflect modern management of ARDS. To some lung pathology and major pulmonary embolism;
those ends, the investigators recorded admissions over second, lung conditions which develop more slowly than
4 weeks to 459 ICUs in 50 countries over 5 continents ARDS, for example, interstitial lung diseases (especially
including 29 144 patients. In total, 3022 (10.4%) cases acute interstitial pneumonia), bronchoalveolar cell carci-
fulfilled ARDS criteria, including almost a quarter of noma, lymphangitis and the pulmonary vasculitides.
those supported with invasive mechanical ventilation.13
Despite this relatively high prevalence and the study’s
focus on ARDS, the syndrome was recognised in only Technical summary
half of the mild ARDS group. Furthermore, in a study The guidelines for the management of adult patients
that reported on 815 patients with at least one risk factor with ARDS were created by a multidisciplinary writing
for ARDS who were admitted to one of 3 Spanish hospi- group constituted by the Joint Standards Committee of
tals over 4 months, 15 out of 53 patients (28%) were not the Faculty of Intensive Care Medicine and the ICS. All
2 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

Open access
Figure 1 Sixty-day and hospital mortality comparing LTV and HTV mechanical ventilation in adult patients with ARDS.
ARDS, acute respiratory distress syndrome; HTV, higher tidal volume; LTV, lower tidal volume.
group members, including lay members, are coauthors of older MA were used if not all the preselected outcomes
the guideline. The group first met in 2013 and completed could be extracted from the most recent MA.
the guidelines in 2018. The guidelines have undergone The guidelines used the internationally recognised
copyright.
both independent external peer review and input from GRADE methodology.17 Group members received
stakeholder organisations. training on the GRADE process and were given a
The process for guideline creation adhered to that of resource pack, which included a practical guide which
the National Institute for Health and Care Excellence was created in- house. GRADE makes recommendations
(NICE). In brief, the writing group first performed a based on patient centred and predetermined outcomes.
scoping exercise on the topic, having decided that the It does not judge the quality of individual randomised
focus should be on effective treatment interventions. Ten controlled trials (RCTs) but makes quality assessments on
topics were chosen based on existing guideline recom- the predetermined outcomes, which, where possible, are
mendations and the experience of committee members. extracted from published MA.18
These included: The following outcomes were chosen by the writing
►► Corticosteroids. group as either of critical or high importance using the
►► ECMO. GRADE methodology:
►► ECCO2R. Mortality (28 day, hospital and 6 month): Critically
►► Fluid strategy. important.
►► High-frequency oscillation ventilation (HFOV). Mortality (1 year): Critically important.
►► Inhaled vasodilators (iVasoD). Length of stay (ICU and hospital): Important.
►► Lung protective ventilation: tidal volume (Vt). Quality of life (at 3 months): Critically important.
►► Neuromuscular blocking agents (NMBA). Quality of life (at 6 months and 1 year): Important.
►► PEEP. Harms (at 3 months, 6 months and 1 year): Important.
►► Prone positioning. GRADE has a transparent methodology and guides
Each topic was developed into a full protocol using the recommendations based on the evidence collected.
PICO (Population, Intervention, Comparison, Outcome) In reality, treatment recommendations are a gradua-
formulation. Search strategies for each topic were then tion. However, in order to aid clinical decision-making,
developed by the group information expert with a focus GRADE converts the continuum into five mutually exclu-
on systematic reviews (SR) and meta-analyses (MA). Each sive categories.17 Recommendations are therefore catego-
topic was assigned to two group members with one acting rised as strongly in favour, weakly in favour (or conditional),
as topic lead. High-quality MA and SR were selected and strongly against or weakly against (conditional). Finally, a
the references placed in an Endnote database. Prese- research recommendation can be made where the estimate
lected outcome data were extracted from these reviews, of the magnitude of effect and its boundaries were so
using the most up-to-date MA where possible. Data from imprecise and wide that further research is likely to make
Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420 3

Open access
a fundamental change to a recommendation. Recom- results of the former have been excluded from this anal-
mendations were made by the whole writing group. The ysis. Eight, high quality SRs with MA, performed between
lead author would present the data and suggest a recom- 2008 and 2014, were identified (see PRISMA chart in
mendation, using GRADE methodology, based on the online appendix A (https://www.ficm.ac.uk/sites/
balance of benefits and harms as detailed in the GRADE default/files/appendix_a_-_prisma_diagrams.pdf).19–26
tables and evidence. The group would then debate the A total of eight RCTs performed between 1985 and 2007
topic and reach a consensus, based on the opinion of the were included in these reviews. The largest single study
majority. enrolled only 180 patients.
A GRADE Summary of Findings table is shown below
based on critical and important outcomes (table 1). A
Corticosteroids
full GRADE evidence table can be found as part of the
PICO question
online appendix B (https://www.ficm.ac.uk/sites/
In adults with ARDS, does the use of corticosteroids,
default/files/appendix_b_-_grade_evidence_tables.pdf).
compared with standard care, affect survival and selected
outcomes?
Analysis of outcomes
Study identification Mortality
The search strategy was predefined as per the online A MA of hospital mortality alone was presented in two
appendix C (https://www.ficm.ac.uk/sites/default/ SRs,19 21 while combined data on both hospital and 60-day
files/appendix_c_-_search_strategies.pdf). The role of mortality were presented in another SR.20 The quality of
corticosteroids in ARDS has been studied in RCT both in evidence supporting the relative risk (RR) of 0.51 (95%
populations at risk of developing ARDS and in the estab- CI 0.24 to 1.09) in hospital mortality with steroids was
lished syndrome. These prevention and treatment trials very low21 (see GRADE evidence profile table 1). There
have been separately analysed in most SR with MA; the was a serious risk of bias with only 75% of the Cochrane
Table 1 Corticosteroids compared to placebo for ARDS
copyright.
Patient or population: adults with ARDS
Settings: intensive care
Intervention: corticosteroids
Comparison: placebo
Illustrative comparative risks (95% CI)
Relative No. of Quality of
Control risk Intervention risk
effect (95% participants evidence
Outcomes Placebo Corticosteroids CI) (studies) (GRADE) Comments
Mortality 526 per 1000 326 per 1000 RR 0.62 561 +--- All studies conducted in
(hospital) (121 to 663) (0.23 to (five studies) VERY LOW the prelung protection
1.26) Due to serious risk strategy era. One study
of bias, serious changed ventilation
inconsistency protocol during the
and serious study, following ARDS
imprecision Net ARMA result
Mortality 500 per 1000 455 per 1000 RR 0.91 725 ++-- Pooled estimate
(hospital or 60 (355 to 590) (0.71 to (eight studies) LOW from studies of
day) 1.18) Due to serious both treatment and
inconsistency preventative steroids
and serious
imprecision
Adverse 350 per 1000 287 per 1000 RR 0.82 494 ++-- Composite of infection;
events (175 to 477) (0.5 to 1.36) (four studies) LOW neuromyopathy;
Due to serious diabetes,
risk of bias gastrointestinal bleeding
and serious and others
imprecision
Adverse Mean—74.31 Mean—10.71 higher 100 +--- Assessed with: cognitive
event: post- (5.22 higher to (one study) VERY LOW function component of
ICU cognitive 16.2 higher) Due to very QLQ-C30
function serious risk of Scale from: 0 to 100,
bias and serious with a higher score
indirectness representing better
cognitive function
ARDS, acute respiratory distress syndrome; ICU, intensive care unit.

Open access
risk of bias recommendations followed. Inconsistency although the group noted that the trials did not include
was also serious with point estimates varying widely, confi- longer term follow-up of survivors. However, the evidence
dence intervals overlapping, a lack of consistent direc- is of low to very low quality from clinical trials, which were
tion of effect and significant heterogeneity (I2 52%). mostly conducted before the current era of lung protec-
Imprecision was also serious. A posthoc power calcula- tive ventilation. In addition, the lack of sufficient power
tion suggests that the pooled studies only had an approx- in any individual study or in the combined MA and the
imately 65% power and a sample size calculation based heterogeneity of the dose, timing and agent used also
on the reported effect size suggested that sample size was influenced the decision. The group believed that a posi-
inadequate (predicted sample size of 474; actual pooled tion of equipoise exists and the research recommenda-
sample size of 341 for hospital mortality). This is likely tion reflects this view.
to be an underestimate of the sample size required, as As a caveat, it is worth mentioning that specific steroid
the effect size is likely to be smaller than the pooled data responsive disorders may mimic ARDS, for example,
suggest due to heterogeneity of the studies. pneumocystis jiroveci pneumonia, acute eosinophilic
A further issue is the fact that the majority of these pneumonia and diffuse alveolar haemorrhage.
studies were performed in the prelung protection
strategy era. The largest ARDS Network steroid study,
Implications for future research
LASARUS, changed its ventilation protocol during the
A large, multicentre study on steroids in established
study to reflect the results of the ARDS Network ARMA
ARDS is currently planned.
low tidal volume study.27
The other hospital mortality analysis also reported
low-quality data with an estimated RR of 0.62 (0.23– Extracorporeal membrane oxygenation
1.26).19 Combining hospital and 60-day mortality gave PICO question
a RR estimate of 0.91 (0.71–1.18) with serious inconsis- In adults with ARDS, does the use of ECMO, compared
tency and indirectness issues including the fact that this with standard care affect survival and selected outcomes?
was a pooled estimate of both preventative and treatment
studies.20
Study identification
The search strategy was predefined as per online appendix
Length of stay
copyright.
C. Eight, relevant SR were identified, of which three
A MA of hospital length of stay was presented in one SR
included a MA28–30 (see PRISMA chart in online appendix
and MA.22 A mean reduction of 4.8 days with steroid treat-
A). When analysing results, we used the most recent SR
ment was reported but the overall quality of the studies
with MA that considered the outcome in question.29 The
was very low.
selected SR with MA included only two RCTs of ECMO
in adults with ARDS. These RCTs were published in 1979
Quality of life
and 2006 and included a total of 270 participants.31 32
This was not reported in the Included MA.
The older RCTs32 did not combine the use of ECMO with
protective low tidal volume mechanical ventilation and
Economic data
so is of little relevance to current practice. Data from this
No economic data were published in the trials included.
RCT and RCTs investigating the use of extracorporeal
carbon dioxide removal (ECCO2R)33 34 were excluded. By
Treatment harms
contrast, we included in our de novo MA two quasi-RCT,
Potential harms of treatment with steroids included
which used genetic matching with replacement to iden-
excess hospital acquired infections, ICU acquired weak-
tify control subjects and compared these with patients
ness and delirium. The only available MA reported a
supported with ECMO in a total of 346 patients, all with
composite analysis of infection, ICU acquired weakness,
pandemic H1N1 2009 influenza A.35 36
diabetes, gastrointestinal bleeding and other compli-
A GRADE Summary of Findings table is shown based
cations.21 The RR reported was 0.82 (0.5–1.36) but the
on critical and important outcomes (table 2). A full
quality of the trials was low.
GRADE evidence table can be found as part of the online
appendix B.
GRADE recommendation statement
The use of corticosteroids in established ARDS should
be the subject of a suitably powered, multicentre RCT
Mortality
with long-term follow-up (GRADE Recommendation:
Hospital mortality was studied in two quasi-RCT in patients
research recommendation).
with H1N135 36 and hospital mortality was combined with
mortality up to 6 months after hospital discharge in the
GRADE recommendation justification RCT (CESAR) that recruited a general adult population
Current evidence includes the possibility of substan- with severe ARDS.31 Point estimates consistently showed a
tial patient benefit and the risk of harm appears small, reduction in mortality in patients supported with ECMO:

Open access
Table 2 ECMO compared to standard care for ARDS
Intervention: ECMO
Comparison: standard care
Relative No. of
effect (95% participants Quality of evidence
Outcomes Usual care ECMO CI) (studies) (GRADE) Comments
Mortality 517 per 1000 324 per 1000 RR 0.64 505 +--- Includes data from
(pooled) (264 to 408) (0.51 to 0.79) (three studies) VERY LOW two quasirandomised
Due to serious risk trials of patients with
of bias and serious influenza A H1N1
indirectness
Adverse event: 0 per 1000 250 per 1000 RR 26.02 249 +---
bleeding (3.68 to (two studies) VERY LOW
184.16) Due to serious risk
of bias and serious
indirectness
ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation.
the risk ratio for hospital mortality was 0.64 (0.51–0.79). Grade recommendation justification
However, owing to the potential bias and lack of gener- The use of ECMO in selected adults suffering severe
alisability in the quasi-RCTs, the quality of evidence was ARDS (defined as a Lung Injury Score of 3 or more or
deemed to be very low. pH<7.20 due to uncompensated hypercapnoea),was
given a weakly positive recommendation based on very
low quality evidence. The most widely used indications
Length of stay
for ECMO are those reported in the CESAR study.31
This was not reported in the included MA.
There is a paucity of data to make this judgement: one
copyright.
RCT remains after excluding studies including patients
Quality of life supported with ECCO2R and one RCT from 1979 in
This was not reported in the included MA. which mechanical ventilation was not protective. Argu-
ably the predominant mechanism through which ECMO
may confer a benefit is by enabling the dramatic reduc-
Economic data
tion of ventilation volumes and pressures, thereby miti-
This was not reported in the included MA. The CESAR
gating ventilator-associated lung injury (VALI).
study alone included both cost utility and cost effective-
Scant evidence, again of very low quality, suggested
ness analyses enabling investigators to predict a lifetime
an increased risk of bleeding associated with the use of
cost per quality-adjusted life year (QALY) for ECMO of
ECMO: consistent with data from the extracorporeal life
£19 252 (CI 7622 to 59 200) at a discount rate of 3.5%.31
support organisation (ELSO), which publishes its registry
data from around 300 centres world-wide. The incidence
Treatment harms of serious bleeding (approximately 15% overall) and
The use of ECMO is associated with the risk of serious intracranial haemorrhage (3.9%) associated with the
bleeding, although this has not been universally reported use of veno-venous ECMO for respiratory failure in adult
or consistently defined in published studies. The risk patients based on data from the ELSO registry from its
ratio for bleeding associated with ECMO was 11.44 inception in 1989 to 2016 has recently been reported.37
(3.11–42.06). The quality of evidence was deemed to be
very low because data were available from two non-ran-
domised studies that only included patients with ARDS Extracorporeal carbon dioxide removal
associated with influenza A (H1N1).35 36 PICO question
In adults with ARDS, does the use of ECCO2R, compared
with standard care affect survival and selected outcomes?
Grade recommendation statement
We do not recommend the routine use of ECMO for all Study identification
patients with ARDS (GRADE Recommendation: weakly The role of ECCO2R in ARDS has been studied in two RCTs
against). We suggest the use of ECMO with lung-pro- in patients with ARDS enrolling 119 subjects. These trials
tective mechanical ventilation in selected patients with have been analysed in SR without MA: there were signifi-
severe ARDS (GRADE Recommendation: weakly in cant difference between the studies in both ECCO2R tech-
favour). nique and conventional ventilator strategy. Consequently,

Open access
Table 3 ECCO2R compared to standard care for acute respiratory distress syndrome
Intervention: ECCO2R
Relative effect
Outcomes (95% CI) No. of participants (studies) Quality of evidence (GRADE) Comments
Mortality No MA conducted 457 +--- Mostly observational studies. Only two RCTs
(hospital) (13 studies) VERY LOW performed. No MA performed as variable
Due to serious risk of bias, approach to ECCO2R and standard ventilator
serious inconsistency, serious strategies. Mortality estimates presented as
indirectness and serious simple descriptions
imprecision 27%–75% (mean 55.5%, SD 47.2 to 60.3)
Adverse events No MA conducted 485 +--- 0%–25% incidence of arterial injury. Higher
(13 studies) VERY LOW incidence of transfusion reported in two
Due to serious risk of bias, studies.
serious inconsistency, serious Complications presented as aggregated
indirectness and serious simple descriptions—0%–25%
imprecision
ECCO2R, extracorporeal carbon dioxide removal.
the SR was not able to perform a meaningful MA. There Grade recommendation statement
were two RCTs performed between 1994 and 2013.33 38 The use of ECCO2R in established ARDS should be the
A GRADE Summary of Findings table is shown based on subject of a suitably powered multicentre RCT with long
critical and important outcomes (table 3). A full GRADE term follow-up and economic analysis (GRADE Recom-
evidence table can be found as part of the online appendix mendation: research recommendation).
B.
Grade recommendation justification
Current evidence is extremely limited and mainly consists
copyright.
of non-randomised prospective and retrospective trials.40–44
Mortality
The substantial differences between the techniques for
The risk of bias in the two RCTs was low. Both studies were
both ECCO2R and conventional ventilation make the
stopped early following planned interim analyses and
two RCTs incomparable. However, there is evidence that
concluded that any difference between control and inter-
ECCO2R can allow ventilation with tidal volumes lower
vention groups was too small to be demonstrated. One
than currently recommended for ARDS and the potential
trial enrolled 79 out of a planned 12033 and the other 40
benefits of this approach should be tested in an appropri-
out of a planned 60.38 In one RCT, in-hospital mortality
ately designed RCT. The group believed that a position of
was 17.5% and 15.4% in the intervention and control
equipoise exists and the research recommendation reflects
groups, respectively.33 The other RCT reported 30-day
this view.
mortality in the intervention group of 66.6% and 57.9%
in the control.38 These were not significantly different.
Implications for future research
Length of stay A large, multicentre study evaluating veno-venous ECCO2R
This was not reported in the included SR. to facilitate lower tidal volume ventilation in patients with
acute hypoxaemic respiratory failure is currently ongoing,
the REST (protective ventilation with veno-venous lung
Quality of life
assist in respiratory failure) trial (http://www.nictu.hscni.
No trial reported on quality of life.
net/ rest-
trial). NICE guidelines on the use of ECCO2R
encourage clinicians to recruit patients to the REST trial.
Economic data
No trial reported on economic data. Fluid management
PICO question
Treatment harms In adults with ARDS, does the use of a conservative fluid
Potential harms of treatment with ECCO2R included strategy, compared with a liberal fluid strategy or standard
bleeding and thrombosis. Complications were dependent care, affect survival or selected outcomes?
on the type of ECCO2R used with approaches which
required arterial cannulation reporting an incidence
of arterial injury from 0% to 25%.39 Blood transfusion
requirements were also increased in the ECCO2R group.39

Open access
Table 4 Conservative compared to liberal fluid management for ARDS
Intervention: conservative fluid strategy
Comparison: liberal fluid strategy
Liberal fluid Conservative fluid effect (95% participants evidence
Outcomes strategy strategy CI) (studies) (GRADE) Comments
Mortality (pooled 311 per 1000 283 per 1000 RR 0.91 1206 ++-- Variable fluid strategies,
up to 60 days) (239 to 332) (0.77 to (five RCTs) LOW fluid balance achieved
1.07) Due to serious and outcome reporting
indirectness and
serious imprecision
Adverse event: 1000 +++- MODERATE Single study. There
AKI (one study) Due to serious were a similar number
imprecision of renal failure free days
between conservative
and liberal fluid
management groups.
In a posthoc analysis
where creatinine was
adjusted for fluid
balance, conservative
fluid management was
associated with lower
incidence of AKI (58%
vs 66%).
Adverse event: 141 per 1000 100 per 1000 RR 0.71 1000 +++- MODERATE Single study
RRT (70 to 139) (0.50 to (one study) Due to serious
0.99) imprecision
copyright.
AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; RRT, renal replacement therapy.
Study identification Analysis of outcomes

The search strategy was predefined as per the online Mortality
appendix C. Of four SR identified,45–48 one recent high Heterogeneity in outcome reporting was evident, with
quality SR with MA addressing the question of optimal two studies reporting mortality at 30 days49 50 and three at
fluid strategy in ARDS was included.45 This review 60 days;51–53 the pooled results showed no effect of fluid
included patients with ARDS, sepsis and SIRS, although balance strategy on mortality.
subgroup data were available for ARDS. The review Moderate quality evidence supported an RR of 0.91
included data from five RCTs in ARDS49–53 performed (95% CI 0.77 to 1.08) for mortality using a conservative
between 2002 and 2014, and ranging from 29 to 1000 rather than a liberal fluid strategy. Although two of the
participants. Significant clinical heterogeneity was evident RCTs included were at high or uncertain risk of bias,52 53
between these studies in terms of intervention strategies, these studies included only 129 of 1206 patients, and thus
fluid balance achieved and outcome reporting. Conserv- overall no serious risk of bias was deemed to be present.
ative fluid strategies included protocolised diuretic use, Serious indirectness was present, in that various treat-
with49 50 or without51 hyperoncotic albumin solutions, ment regimens were compared, including a comparison
minimisation of fluid intake51 and the use of extravas- of hyperoncotic albumin versus placebo as an adjunct
cular lung water (EVLW) measurements to guide fluid to diuretic therapy,50 and of EVLW-guided with PCWP-
therapy.52 Liberal fluid strategies varied from a protocol- guided fluid therapy.53 Exclusion of these studies made
ised fluid administration strategy, which approximated little difference to the point estimate. As confidence
the usual care arm of previous large trials in ARDS,51 use intervals around the point estimate were wide, neither
of furosemide without hyperoncotic albumin50 and use clinically important benefit nor harm could be excluded.
of pulmonary capillary wedge pressure (PCWP) to guide
fluid administration.52 One study did not define conserv- Length of ICU stay
ative and liberal fluid strategies in detail.53 Very low quality evidence for a reduction in length of
A GRADE summary of findings table is shown for crit- ICU stay with a conservative fluid strategy was provided by
ical and important outcomes (table 4). A full GRADE two small RCTs including 129 patients.52 53 Both studies
evidence table can be found as part of the online were at very serious risk of bias due to lack of blinding
appendix B. and other methodological flaws. One study52 compared

Open access
EVLW-guided with PCWP-guided fluid therapy, neither Grade recommendation justification
of which is commonly used clinically, and a clinically Despite the low quality of evidence for the majority of
important difference in fluid balance between groups outcomes, and the results being driven largely by a single
was absent. The population, intervention and compar- trial,51 conservative fluid management may be beneficial
ator in the other study were not reported in detail.53 The without evidence of harm. We therefore suggest that in
small number of patients in these studies also led to very adult patients with ARDS, clinicians consider the use of
serious imprecision. a conservative fluid strategy which uses fluid restriction,
diuretics and possibly hyperoncotic albumin to avoid
a positive fluid balance in preference to a liberal fluid
Length of hospital stay
strategy.
A single RCT50 provided low-quality evidence for the
absence of an effect of fluid strategy on length of hospital
stay. Very serious imprecision was present due to a lack of
Ventilation high frequency oscillatory
statistical power to exclude a clinically important differ-
PICO question
ence on this outcome.
In adults with ARDS, does the use of HFOV, compared
with standard care, affect survival and other selected
Quality of life outcomes?
Study identification
Economic data
The search strategy was predefined as per online
No trial reported on economic data.
appendix C. The role of HFOV in ARDS with moderate
to severe hypoxaemia has been studied in six RCTs
Treatment harms published between 2002 and 2013.56–61 Two recent RCTs
Acute kidney injury incidence enrolled a disproportionate number of patients—1343
Incidence of acute kidney injury (AKI) was felt to be out of 1608 patients (795 patients in one and 548 in
important as this represents a potential harm associated the other). There have been an additional two RCTs of
with a conservative fluid strategy. A single large RCT51 HFOV combined with tracheal gas insufflation.62 63 These
copyright.
provided low quality evidence for similar numbers of trials have been analysed in three SRs with MA.64–66
AKI-free days with conservative and liberal fluid strate- Data were analysed from two of these: the most recent
gies, and a posthoc analysis of this trial54 suggested a MA was used first,64 supplemented with additional data
reduction in AKI incidence with a conservative fluid from previous studies.65 One MA was excluded as it
strategy using creatinine measurements corrected for combined results of RCTs with HFOV and tracheal gas
changes in volume of distribution. insufflation with those of RCTs with HFOV alone.66
A GRADE Summary of Findings table is shown below
Requirement for renal replacement therapy based on critical and important outcomes (table 5). A
It was considered that requirement for renal replace- full GRADE evidence table can be found as part of online
ment therapy (RRT) represented a potential harm from a appendix B.
conservative fluid strategy. Moderate quality evidence for
a reduction in the requirement for RRT with a conserv-
ative fluid strategy was provided by a single large RCT51 Analysis of outcomes
(RR 0.71, 95% CI 0.50 to 0.99). Mortality
The RR of death associated with HFOV was 1.218 (0.925
Cognitive dysfunction to 1.604). The evidence was judged to be of moderate
A posthoc analysis of a small subgroup of patients from quality.64 Of the RCTs contributing to the two MAs,
the FACTT trial found conservative fluid strategy to be an five demonstrated no difference in mortality between
independent risk factor for long-term cognitive dysfunc- HFOV and conventional ventilation,56–61 while one of
tion following ARDS.55 One RCT of uncertain risk of bias the larger RCTs demonstrated increased mortality in
found better cognitive outcome scores with conservative the HFOV arm.59 The overall risk of bias in included
fluid strategy than with liberal fluid strategy,53 although studies was low with the exception of two studies where
the duration of follow-up and details of the intervention crossovers accounted for more than 10% of the study
were not described. group.56 58 Inconsistency was serious with point estimates
varying widely, confidence intervals overlapping, a lack
of consistent direction of effect and significant heteroge-
Grade recommendation statement neity (I2=63.1%, p=0.028).
We suggest the use of a conservative fluid strategy in
patients with ARDS (GRADE recommendation: weakly in Length of stay
favour). This was not reported in the included SR.

Open access
Table 5 HFOV compared to usual care for ARDS
Intervention: HFOV
Outcomes Standard care HFOV CI) (studies) (GRADE) Comments
Mortality (ICU) 308 per 1000 442 per 1000 RR 1.22 1321 +++- Changes in
(308 to 447) (0.93 to 1.60) (three studies) MODERATE conventional
Due to moderate ventilation
inconsistency and strategies
mild indirectness accounted for
heterogeneity
Mortality (30 436 per 1000 453 per 1000 RR 1.04 1580 +++- Changes in
day) (362 to 571) (0.83 to 1.31) (five studies) MODERATE conventional
Due to moderate ventilation
inconsistency and strategies
mild indirectness accounted for
heterogeneity
Adverse events: 122 per 1000 147 per 1000 RR 1.205 752 ++-- Barotrauma
barotrauma (101 to 212) (0.834 to (four studies) LOW variably defined
1.742) Due to serious
imprecision
Adverse events: 102 per 1000 77 per 1000 RR 0.557 757 ++-- Oxygenation failure
oxygen failure (61 to 89) (0.351 to (three studies) LOW variably defined.
0.884) Due to serious
imprecision
ARDS, acute respiratory distress syndrome; HFOV, high-frequency oscillatory ventilation.
copyright.
Quality of life one RCT demonstrated an increase in mortality with
No trial reported on quality of life. HFOV.
Economic data
Inhaled vasodilators
No trial reported on economic data.
PICO question
In adults with ARDS, does the use of inhaled vasodi-
Treatment harms
lators (iVasoD), compared with standard care, affect
Potential harms of HFOV were reported including baro-
survival and selected outcomes?
trauma, hypotension and oxygenation failure. The RR of
barotrauma was reported from four studies enrolling 752
subjects as 1.205 (95% CI 0.834 to 1.742); however, the Study identification
studies used a variable definition of barotrauma.64 The The search strategy was predefined as per online
RR of hypotension was reported as 1.326 (95% CI 0.271 appendix C. The role of the iVasoD nitric oxide (iNO) in
to 6.476) and these data were derived from three studies the management of ARDS has been assessed in multiple
enrolling 237 patients.64 Oxygenation failure in the MA RCT, which have been analysed in subsequent SR with
included 757 patients from three studies with a RR for MA. No studies examining the role of nebulised prosta-
HFOV of 0.557 (95% CI 0.351 to 0.884).64 cyclin in adults with ARDS were identified by Cochrane
reviewers in 2010.67
Three SR with MA were identified from which data
were analysed (see PRISMA chart in online appendix
We do not recommend the use of HFOV in the manage-
A).68–70 Mortality data were analysed from nine RCTs71–79
ment of patients with ARDS (GRADE recommendation:
published between 1998 and 2004, including 1142 partic-
strongly against).
ipants. Exclusion criteria for RCT included: >50% cross-
over between iNO and placebo groups and unequal
Grade recommendation justification distribution of other rescue therapies between treatment
The use of HFOV for the management of ARDS was given and control groups. Limited information on possible
a GRADE recommendation of strongly against based harms was available: data from four RCTs71 73 77 78 provided
on moderate quality evidence. Current evidence from specific information regarding nephrotoxicity associated
multiple RCTs demonstrated no benefit from HFOV and with the use of iNO.

Open access
Table 6 iVasoD compared to placebo or usual care for ARDS
Intervention: iNO for all studies
Comparison: placebo or usual care
Control risk Intervention risk Relative No. of Quality of
Placebo/Usual effect participants evidence
Outcomes care iVasoD (95% CI) (studies) (GRADE) Comments
Mortality 315 per 1000 346 per 1000 RR 1.10 1142 ++-- Six out of nine studies
(pooled) (296 to 406) (0.94 to (nine studies) LOW compared iNO with usual
1.29) Due to care rather than placebo
serious risk Highly variable dose
of bias and and duration of iNO and
serious inclusion criteria
indirectness
Adverse 124 per 1000 191 per 1000 RR 1.55 919 ++-- Highly variable dose
event: renal (142 to 258) (1.15 to (four studies) LOW and duration of iNO and
dysfunction 2.09) Due to inclusion criteria
serious risk Variable criteria used to
of bias and define renal dysfunction
serious
indirectness
ARDS, acute respiratory distress syndrome; iNO, iVasoD, inhaled nitric oxide; iVasoD, inhaled vasodilators.
A GRADE Summary of Findings table is shown below Length of stay
copyright.
based on critical and important outcomes (table 6). A No MA available.
full GRADE evidence table can be found as part of online
appendix B. Quality of life
Analysis of outcomes Economic data

Mortality No trial reported on economic data.
Mortality at hospital discharge was used for analysis
where available. Otherwise these data were combined Treatment harms
with mortality at discharge from the ICU or 28–30 days The administration of iNO was associated with an
after randomisation. The quality of evidence supporting increased incidence of renal dysfunction in four trials
the RR of 1.10 (95% CI 0.94 to 1.29: p=0.24) in the representing 80% of the patients recruited into the nine
first treatment analysis was low (see GRADE evidence studies analysed above (risk ratio 1.50, 1.11 to 2.02). The
profile table). In only 3/9 studies72 78 79 was placebo gas quality of the evidence supporting the association was
(nitrogen) administered to the control group, creating judged to be low based on the factors outlined above and
a serious risk of bias in the other six studies. There was the variable criteria used to define renal dysfunction,
serious indirectness in the nine studies analysed owing to although the consistency between trials was good.
variability in inclusion criteria including marked devia-
tion from AECC criteria for diagnosing ALI/ARDS and
variable iNO treatment regimens. Data from studies using
We do not suggest using iNO in patients with ARDS
different doses of iNO were combined. These variable
(GRADE Recommendation: weakly against).
doses and duration of treatment, which may be consid-
ered to be too high and too long respectively, constitute a
serious source of indirectness. Consistency was good with Grade recommendation justification
confidence intervals overlapping, a consistent direction The recommendation that iNO is not used for adult
of effect and a very low heterogeneity.70 patients with ARDS is based on low quality but consistent
Subgroup analysis from 7/9 trials did not support evidence suggesting a lack of mortality benefit and an
the hypothesis that iNO conferred a survival benefit in association with renal dysfunction. While the studies
patients with severe ARDS (PaO2 to FiO2 ratio of <20 examining the role of iNO in ARDS are imperfect, further
kPa). trials would be given a low priority. The possible use of

Open access
iNO in patients with severe right ventricular dysfunction (RR 0.87, 95% CI 0.75 to 1.01, p=0.07) with moderate, but
or extreme hypoxaemia for short periods, while more non-significant heterogeneity (I2 48%, p=0.13). Pooled
long-term rescue strategies (such as ECMO) are insti- data for hospital mortality showed a statistically signifi-
tuted, fall outside the scope of this guideline. cant reduction in risk of death (RR 0.83, 95% CI 0.71 to
0.98, p=0.02) associated with lower tidal volume ventila-
tion, whereas a non-significant increase in risk was found
Mechanical ventilation at lower tidal volume at 60 days (RR 1.23, 95% CI −0.80 to 1.89, p=0.35) based
PICO question on data from a single study with relatively few patients,
In mechanically ventilated adult patients with ARDS, do in which body weight was not corrected according to the
lower tidal volumes compared with higher, conventional ideal or predicted standard (http://www. ardsnet.
org/
tidal volumes affect survival and other related outcomes? files/pbwtables_2005-02-02.pdf).
Study identification ICU length of stay

The search strategy was predefined as per online appendix The pooled effect from two studies90 91 showed no signif-
C. Seven, full text, SR were assessed for eligibility. We icant difference in length of ICU stay (mean difference
excluded four reviews: three did not contain the full 4.79 days, 95% CI −2.06 to 11.63, p=0.17) (figure 2).
complement of published trials80–82 and one contained
studies of patients without ARDS.83 The remaining three Hospital length of stay
reviews84–86 each contained the six RCT that met the There was no difference in hospital length of stay
PICO inclusion criteria. We extracted the mortality data reported by one study90 (mean difference 6.30 days, 95%
provided by Petrucci 201385 (the most recent published CI −7.53 to 20.13, p=0.37).
review) to the GRADE profiler. In addition, we reviewed
the published papers and extracted additional outcomes Quality of life
that were relevant to the guidelines, but not reported in No trial reported on quality of life.
the three SR.
The Petrucci 2013 review included six multi-centre Economic data
RCT published from 1998 to 2006 that included a total of No trial reported on economic data.
copyright.
1297 patients. Within-trial sample sizes ranged from 52 to
861 patients. Trials were conducted in North and South
Lower tidal volume with higher PEEP versus higher,
America and Europe. Four trials87–90 compared lower
conventional tidal volume with lower PEEP
tidal volumes (range <6–8 mL/kg) and restricted airway
Mortality: 28-day, ICU and hospital
pressures (plateau pressure<30 cmH2O) with higher
Two studies reported mortality. At 28 days, one study92
tidal volumes (range 9–15 mL/kg) and airway pressures
showed a significant reduction in risk of death in the
(plateau pressure <50–60 cmH2O). The Amato 1998 92
lower tidal volume and higher PEEP group (RR 0.54,
and Villar 2006 93 trials compared lower tidal volume
95% CI 0.31 to 0.91, p=0.02). Similarly, pooled data
with higher PEEP, where possible set just above the lower
from two studies showed a significant reduction in risk
inflection point of a pressure-volume curve, and higher
of ICU mortality (RR 0.57, 95% CI 0.40 to 0.82, p=0.002)
tidal volume with lower PEEP: these studies investigating
and hospital mortality (RR 0.62, 95% CI 0.44 to 0.87,
the composite intervention of lower tidal volume and
p=0.006).92 93 In both cases, the evidence was downgraded
higher PEEP were analysed separately.
to low because of imprecision (relatively few patients,
We provide Forest plots to show the separate MA for
156 in total), and indirectness of evidence (methodolog-
the comparisons of (1) lower versus higher tidal volumes
ical flaws—body weight was not corrected in one study;
with similar PEEP and (b) lower tidal volumes with
and lack of generalisability based on the unusually high
higher PEEP versus higher tidal volume with lower PEEP.
mortality rate of the conventional ventilation group).
A GRADE Summary of Findings table is shown based on
critical and important outcomes (table 7). A full GRADE
evidence table can be found as part of online appendix Grade recommendation statement
B. We recommend the routine use of lower tidal volumes
for the management of patients with ARDS (GRADE
Recommendation: strongly in favour).
Lower versus higher tidal volume with similar PEEP
Mortality Grade recommendation justification
In this comparison, four studies reported mortality at The recommendation to use lower tidal volume (less
varying time-points: 60 days91 and hospital discharge than or equal to 6 mL/kg predicted body weight) venti-
(figure 1).87–89 Pooled data from the four trials showed lation with a plateau pressure less than or equal to 30
no significant difference between lower and higher tidal cmH2O is strong despite moderate quality of evidence
volume groups in risk of death including all time-points for hospital mortality and barotrauma, but low quality of

Open access
Table 7 Lower tidal volume compared with higher tidal volume (at similar PEEP) for ARDS
Intervention: lower tidal volume
Comparison: higher, conventional tidal volume
Illustrative comparative risks* (95% CI)
Relative No. of
Higher tidal effect participants Quality of evidence
Outcomes volume Lower tidal volume (95% CI) (studies) (GRADE) Comments
Mortality (60 379 per 1000 467 per 1000 (303 to RR 1.23 116 ++--
day) 717) (0.8 to (one study) LOW
1.89) Due to inconsistency and imprecision
Mortality 408 per 1000 338 per 1000 RR 0.83 1033 +++-
(hospital) (290 to 400) (0.71 to (three studies) MODERATE
0.98) Due to serious indirectness
Adverse 30 per 1000 35 per 1000 RR 1.17 1149 +++-
event: (19 to 65) 0.63 to (four studies) MODERATE
barotrauma 2.18 Due to serious indirectness
Lower tidal volume and higher PEEP compared with higher tidal volume and lower PEEP for ARDS
Intervention: lower tidal volume and higher PEEP (LV/PEEP)
Comparison: higher tidal volume and lower PEEP (HV/PEEP)
Illustrative comparative risks*
(95% CI)
No. of
Low PEEP/ High PEEP/ Low Relative effect participants Quality of evidence
Outcomes HIGH TV TV (95% CI) (studies) (GRADE) Comments
copyright.
Mortality (ICU) 594 per 1000 339 per 1000 RR 0.57 148 ++-- ARDS Net ARMA study
(238 to 487) (0.4 to 0.82) (two studies) LOW control group had higher
Due to inconsistency TVs (11.5/12) than controls
and imprecision in the other four studies
Mortality (28 day) 708 per 1000 383 per 1000 RR 0.54 53 ++--
(220 to 645) (0.31 to 0.91) (one study) LOW
Due to inconsistency
and imprecision
Mortality (hospital) 609 per 1000 377 per 1000 RR 0.62 148 ++--
(268 to 530) (0.44 to 0.87) (two studies) LOW
and imprecision
Adverse events: 458 per 1000 587 per 1000 RR 1.28 53 ++--
nosocomial (344 to 999) (0.75 to 2.18) (one study) LOW
pneumonia Due to inconsistency
and imprecision
Adverse events 214 per 1000 165 per 1000 RR 0.77 254 ++--
(105 to 261) (0.49 to 1.22) (two studies) LOW
and imprecision
ARDS, acute respiratory distress syndrome; ICU, intensive care unit; PEEP, positive end-expiratory pressure.
evidence for 60-day mortality. The evidence was down- data from ARDS prevention studies95 have resulted in its
graded for serious indirectness for hospital mortality, and universal acceptance as a gold standard of care.
for inconsistency and imprecision for 60 day mortality.
For example, the beneficial effects of low tidal volume
ventilation were only seen in one large trial and the
means of managing respiratory acidosis in the ARDS Neuromuscular blocking agents
Network ARMA trial87 is not generally applied. However, PICO question
a lack of adverse effects associated with the intervention, In adults with ARDS, does the use of NMBA, compared
strong mechanistic rationale for its use94 and supportive with standard care, affect survival and selected outcomes?

Open access
Figure 2 ICU length of stay comparing LTV and HTV mechanical ventilation in adult patients with ARDS. ARDS, acute
respiratory distress syndrome; HTV, higher tidal volume; ICU, intensive care unit; LTV, lower tidal volume.
Study identification GRADE evidence table can be found as part of online

The search strategy was predefined as per online appendix B.
appendix C. The only NMBA studied in an RCT consid-
ering outcomes relevant to our PICO question was cisatra-
curium besylate. Four SR were identified,96–99 published Analysis of outcomes
between 2012 and 2015, of which only two included Mortality
MA.96 97 When analysing results, we used the most recent Mortality (pooled 28 day, ICU and hospital mortality)
SR with MA96 that considered the outcome in question. was reported in all three RCTs100–102 with point esti-
The two selected SR with MA included the three RCTs mates showing a reduction in mortality at each of these
of NMBAs that were identified, both of which compared time points. However, in each of these RCT, the 95% CI
a continuous 48 hours infusion of cisatracurium with for the risk ratio reached or crossed the no effect line.
standard care. These RCTs were published between 2004 When mortality data from these RCTs were pooled in MA
and 2010 and included a total of 431 participants from (with a total of 431 participants), the CI was narrowed
20 French ICUs. to show a significant reduction in mortality at each of
A GRADE Summary of Findings table is shown based these time points. The risk ratios for 28 day, ICU and
on critical and important outcomes (table 8). A full hospital mortality were 0.66, 0.70 and 0.72, respectively,
copyright.
Table 8 NMBAs compared to placebo for ARDS
Intervention: NMBAs, cisatracurium infusion in all studies
Comparison: placebo
effect participants evidence
Outcomes Placebo NMBAs (95% CI) (studies) (GRADE) Comments
Mortality (ICU) 447 per 1000 313 per 1000 RR 0.70 431 +++- MODERATE All trials studied a
(246 to 398) (0.55 to (three studies) Due to serious risk 48 hours infusion of
0.89) of bias and serious cisatracurium besylate
indirectness
Mortality (28 389 per 1000 257 per 1000 RR 0.66 431 +++- See above
day) (195 to 339) (0.50 to (three studies) MODERATE
of bias and serious
indirectness
Mortality 471 per 1000 339 per 1000 RR 0.72 431 +++- See above truncated at
(hospital) (273 to 429) (0.58 to (three studies) MODERATE 90 days
of bias and serious
indirectness
Adverse 298 per 1000 322 per 1000 RR 1.08 431 +--- Lack of robust screening
events: ICU (247 to 420) (0.83 to (three studies) VERY LOW for weakness in first two
acquired 1.41) Due to very RCTs. Third RCT only
weakness serious risk of assessed weakness until
bias, serious ICU discharge. Screening
inconsistency methods differed greatly
and serious between RCT
indirectness
ARDS, acute respiratory distress syndrome; ICU, intensive care unit; NMBA, neuromuscular blocking agents; RCT, randomised controlled trial.

Open access
suggesting a significant reduction in the risk of mortality benefit, it was only by pooling these data in MA that these
with this intervention. findings reached statistical significance. There are also
Although these results showed a good level of consis- concerns over the ineffective blinding of caregivers to
tency and precision, there are important concerns over study group allocation in the clinical trials and concerns
the risk of bias and indirectness in the contributing RCT. that the potential association of NMBA and ICU-acquired
All three studies, which were conducted by the same weakness was not studied in a robust manner.
team of investigators in France, have been criticised for
the lack of effective blinding of caregivers to study group
allocation. In two of the studies,100 102 no attempt was Positive end-expiratory pressure
made to blind caregivers while, in the third,101 it is ques- PICO question
tionable whether blinding was effective. It has also been In adult patients with ARDS, does mechanical ventilation
noted that there is considerable overlap of authorship with higher PEEP, compared with standard (lower) PEEP
of the most recent SR and the contributing RCT. One improve survival, and selected outcomes?
of the contributing RCTs101 included only patients with
severe ARDS (P/F ratio<20 kPa) within the first 48 hours, Study identification
leading to our assessment of ‘serious’ indirectness of the The search strategy was predefined as per online appendix
findings for ARDS as a whole. C. Six high-quality SR with MA were identified (see
PRISMA chart in online appendix A). These used data
Length of stay from a total of seven clinical trials,92 93 103–107 published
This was not reported in the included SR. between 1998 and 2009. The largest single study enrolled
983 patients.105 Data from three MA form the basis of the
Quality of life recommendation,108–110 with the most recent used where
This was not reported in the included SR. possible for outcomes of interest. Where this MA did not
provide information on relevant outcomes, alternative
Economic data MA were used.
This was not reported in the included SR. A GRADE summary of findings table is shown based on
critical and important outcomes (table 9). A full GRADE
Treatment harms
copyright.
evidence table can be found as part of online appendix
A key concern for the use of NMBA in ICU is the B.
presumed risk of increased ICU-acquired weakness with
their use. Although the risk of ICU-acquired weakness
was not found to be significantly increased on MA (RR Analysis of outcomes
1.08; 95% CI 0.83 to 1.41), these findings are severely Mortality
limited by the lack of robust screening measures in two of A MA of hospital mortality alone was presented in the
the contributing RCT,100 102 and by the lack of follow-up most recent SR assessing the impact of higher PEEP in
beyond ICU discharge in the final RCT101 ARDS.110 The quality of evidence supporting the RR of
0.90 (0.81–1.01) was deemed moderate, as there were
different strategies used between the trials to set PEEP.
The mean PEEP levels in each arm of the three studies
We do not suggest using NMBAs for all patients with
are presented in table 10.
ARDS (GRADE Recommendation: weakly against). We
Mortality within 28 days of randomisation was presented
suggest the use of cisatracurium besylate by continuous
in the same MA, and the quality of evidence supporting
48 hours infusion in patients suffering early moderate/
the RR of 0.83 (0.67–1.01) was low, as the analysis included
severe ARDS (P/F<20 kPa: GRADE Recommendation:
trials which incorporated low tidal volume ventilation in
weakly in favour).
the high PEEP arm, while the control group were venti-
lated with a low PEEP, high tidal volume strategy.
Grade recommendation justification Individual patient data MA of three RCT (table 10)
The use of cisatracurium besylate in adults suffering evaluating high vs low PEEP showed a reduction in
early, severe ARDS was given a weakly positive recommen- ICU mortality (up to day 60) in patients with moderate
dation based on moderate evidence quality. The group or severe ARDS (P/F<27 kPa): RR 0.85 (0.76 to 0.95).
felt it was appropriate to recommend this management There is moderate quality of evidence supporting this
protocol because it was the only one studied by RCT. Due assessment, again because different strategies to set
to the nature of this intervention, it should only be given PEEP levels were used. This analysis is supported by a
to patients who are adequately sedated and receiving MA of three randomised trials that, with low quality of
invasive ventilation. As such, it would have been difficult evidence, reported a reduced ICU mortality in patients
to recruit patients with mild ARDS. with moderate or severe ARDS (RR 0.67 (0.48 to 0.95).110
Although it is reassuring that in all three RCTs the Additional individual patient data MA evaluating the
point estimate of treatment effect indicated a survival effect of high PEEP on hospital mortality in three studies

Open access
Table 9 Higher PEEP compared to lower PEEP for ARDS
Intervention: higher PEEP
Comparison: lower PEEP
Outcomes Lower PEEP Higher PEEP CI) (studies) (GRADE) Comments
Mortality (hospital) 369 per 1000 332 per 1000 RR 0.90 2299 +++- Different
(299 to 373) (0.81 to 1.01) (three studies) MODERATE strategies used
Due to serious to set PEEP
inconsistency between trials
Mortality (28 day) 330 per 1000 274 per 1000 RR 0.83 1921 ++-- Includes
(221 to 334) (0.67 to 1.01) (five studies) LOW studies whose
Due to very intervention
serious compares high
inconsistency vs low tidal
volume
Subgroup analysis in 561 per 1000 377 per 1000 RR 0.67 205 ++-- Includes
patients with moderate/ (270 to 534) (0.48 to 0.95) (three studies) LOW studies whose
severe ARDS (p/F<27 Due to very intervention
kPa) (subgroup analysis) serious compares high
Mortality (ICU) inconsistency vs low tidal
volume
Subgroup analysis in 391 per 1000 352 per 1000 RR 0.90 1892 +++- Different
patients with moderate/ (317 to 319) (0.81 to 1) (three studies) MODERATE strategies used
severe ARDS (p/F<27 Due to serious to set PEEP
kPa) (individual patient inconsistency between trials
data MA)
Mortality (hospital)
copyright.
Subgroup analysis in 366 per 1000 311 per 1000 RR 0.85 1892 +++- Different
patients with moderate / (278 to 347) (0.76 to 0.95) (three studies) MODERATE strategies used
severe ARDS (P/f<200) Due to serious to set PEEP
(Individual patient data inconsistency between trials
MA)
Mortality (ICU up to
day 60)
Adverse event: 90 per 1000 87 per 1000 RR 0.97 2504 +--- Wide CI; 95%
barotrauma (59 to 127) (0.66 to 1.42) (five studies) VERY LOW CI beyond 25%
Due to very threshold
serious
inconsistency
and serious
imprecision
ICU free days 781 751 Mean +++- Better indicated
difference MODERATE by lower value
0.04 higher Due to wide CI; 95%
(1.03 lower to imprecision CI beyond 25%
1.1 higher) threshold
ARDS, acute respiratory distress syndrome; ICU, intensive care unit; PEEP, positive end-expiratory pressure.
reported a RR 0.90 (0.81 to 1), with evidence supporting

this finding regarded as moderate (see GRADE evidence
Table 10 PEEP values at day 1 in clinical trials profile table).108
Control-group
Study High-PEEP arm (cmH2O) (cmH2O)
Length of stay
ALVEOLI105 14.7±3.5 8.9±3.5
In a MA of two trials, a high PEEP strategy was not asso-
LOV 105 15.6±3.9 10.1±3.1
ciated with a significant reduction in ICU-free days (0.04
ExPRESS106 14.6±3.2 7.1±1.8 (95% CI −1.03 to 1.1)). This is supported by a moderate
Values are mean+SD. evidence base given the wide confidence interval that
PEEP, positive end-expiratory pressure. extends beyond the 25% threshold.

Open access
Quality of life Analysis of outcomes
This was not reported in the included SRs. Mortality
Mortality (defined as overall mortality at the longest
Economic data available follow-up) was significantly reduced with prone
This was not reported in the included SRs. positioning (RR 0.9; 95% CI 0.82 to 0.96, 8 studies, 2141
patients) with very low quality of evidence supporting this
Treatment harms RR. All trials demonstrated performance bias, because
A higher PEEP ventilation strategy was not associated of the impossibility of blinding patients and carers with
with increased rates of air leaks (RR 0.97 (0.66 to 1.42)), respect to the intervention. All trials also demonstrated
with the evidence supporting this finding deemed very detection bias, where outcome assessors were not blinded
low because of the difference in tidal volume strategies to intervention allocation. One RCT additionally demon-
assessed between the intervention and control arms of strated selection bias124 and three separate trials suffered
some studies, and the imprecision of the results.110 from attrition bias125–127 according to the Cochrane risk of
bias recommendations.128 Inconsistency was very serious,
with varied point estimates, overlapping confidence inter-
Grade recommendations
vals with high and significant levels of heterogeneity. There
We suggest the use of high PEEP strategies for patients
was also serious indirectness as the cohort of trials included
with moderate or severe ARDS (P/F ratio <27 kPa:
subgroups receiving additional interventions known to
GRADE Recommendation: weakly in favour).
demonstrate a mortality benefit.
Subgroup analysis demonstrated that prone positioning
Grade justification in combination with lung-protective ventilation (low tidal
We identified low-quality evidence to support the use of volume ventilation, 6–8 mL/kg body weight) demonstrated
higher PEEP strategies in the ventilation of patients with a significant reduction in mortality (RR 0.73; 95% CI 0.62 to
moderate or severe ARDS. Evidence was downgraded 0.86) compared with patients receiving prone positioning
because of inconsistency caused by differences between and no lung-protective ventilation (RR 1.01; 95% CI 0.9 to
individual studies in the strategy to set the level of PEEP, 1.13), supported by moderate quality evidence. These find-
while some trials compared lower tidal volume venti- ings may be influenced by inclusion of one trial enrolling a
lation as part of a ventilator strategy that incorporated sizeable patient cohort with more severe ARDS (P/F ratio
copyright.
higher PEEP levels. The recommendation to consider <20 kPa, FiO2>0.6)129 which showed larger differences
the use of higher PEEP in patients with at least moderate in mortality rates between patients managed prone and
ARDS is based on subgroup and individual patient data supine in the setting of lung-protective ventilation.
MA, providing less robust evidence than a RCT inves- Subgroup analysis based on the duration of prone posi-
tigating higher PEEP in this patient group. The risk of tioning found that over 12 hours of prone positioning was
barotrauma as a result of the use of higher PEEP for associated with significantly reduced mortality (>12 hour,
patients with at least moderate or severe ARDS cannot be RR 0.75, 95% CI 0.65 to 0.87;<12 hour, RR 1.03, 95% CI 0.91
excluded because this risk has not been quantified in this to 1.17), again supported by moderate quality evidence.
population. The quality of this evidence is also limited by
inconsistency as the MA included trials of high PEEP with Length of stay
different tidal volume strategies. ICU length of stay was only examined in two older MAs.112 123
However, these data could not be extracted, as pooled anal-
Prone positioning yses included either confirmed or potential paediatric data.
PICO question No other trial examined hospital length of stay.
In adults with ARDS, does the use of prone positioning,
compared with standard care, affect survival and selected Quality of life
outcomes? No trial reported on health-related quality of life.
Study identification Economic data

The search strategy was predefined as per online appendix No trial reported on economic data.
C. Fourteen eligible SRs investigating the effect of prone
positioning in ARDS98 111–123 (see PRISMA chart in online Treatment harms
appendix A) were identified. Twelve reviews included Overall, the pooled risk of any adverse event with prone
a MA.98 111–113 115 117–123 The most recently published of positioning was significantly increased (RR 1.10; 95% CI
these was used for data extraction.120 1.01 to 1.12). Where a more detailed analysis of adverse
A GRADE Summary of Findings table is shown based events was conducted, endotracheal tube displacement
on available evidence for critical and important outcomes (RR 1.33; 95% CI 1.02 to 1.74), the incidence of pressure
(table 11). A full GRADE evidence table can be found as sores (1.23; 95% CI 1.07 to 1.41) and loss of venous access
part of online appendix B. (RR 1.98; 95% CI 1.11 to 3.55) were significantly increased.

Open access
Table 11 Prone positioning compared with standard care for ARDS
Relative No. of
effect participants Quality of
Outcomes Standard Care Prone Positioning (95% CI) (studies) evidence (GRADE) Comments
Mortality (pooled) 467 per 1000 421 per 1000 RR 0.90 2141 +--- Failure to blind outcome, failure of
(383 to 458) (0.82 to (eight studies) VERY LOW allocation concealment, and incomplete
0.98) Due to serious risk outcome data
of bias, very serious Includes sub-groups receiving
inconsistency and additional interventions known to
serious indirectness demonstrate a potential mortality
benefit
Subgroup 447 per 1000 326 per 1000 RR 0.73 910 +++- MODERATE Failure to blind outcome, failure of
analysis (277 to 384) (0.62 to (five studies) Due to serious risk allocation concealment, and incomplete
Prone positioning 0.86) of bias outcome data
with lung
protective
ventilation
Mortality
Subgroup 483 per 1000 488 per 1000 RR 1.01 1231 +++- MODERATE See above
analysis (435 to 546) (0.9 to (three studies) Due to serious risk
Prone positioning 1.13) of bias
without lung
protective
ventilation
Mortality
analysis (311 to 416) (0.65 to (five studies) Due to serious risk
for more than 12
hours
Mortality
copyright.
analysis (416 to 535) (0.91 to (three studies) Due to serious risk
for less than 12
hours
Mortality
Adverse events 188 per 1000 207 per 1000 RR 1.10 7377 +--- Failure to blind outcome, failure of
(pooled) (190 to 226) (1.01 to (seven studies) VERY LOW allocation concealment, and incomplete
1.2) Due to serious outcome data
risk of bias and
very serious
inconsistency
Adverse events: 278 per 1000 281 per 1000 RR 1.01 1599 +--- Failure to blind outcome, failure of
cardiac events (242 to 325) (0.87 to (three studies) VERY LOW allocation concealment, and incomplete
1.17) Due to serious outcome data
risk of bias and Cohort includes subgroups receiving
very serious additional interventions known to
inconsistency demonstrate a potential mortality
benefit for example, lung- protective
ventilation
Adverse events: 101 per 1000 134 per 1000 RR 1.33 1597 ++-- See above
endotracheal (103 to 176) (1.02 to (five studies) LOW
tube 1.74) Due to serious risk
displacement of bias and serious
imprecision
ventilator- (176 to 270) (0.71 to (four studies) LOW
associated 1.09) Due to serious risk
pneumonia of bias and serious
imprecision
pressure sores (402 to 529) (1.07 to (two studies) LOW
of bias and serious
imprecision
Continued

Open access
Table 11 Continued
Relative No. of
effect participants Quality of
Outcomes Standard Care Prone Positioning (95% CI) (studies) evidence (GRADE) Comments
pneumothorax (40 to 87) (0.59 to (four studies) LOW
of bias and serious
imprecision
Adverse events: 49 per 1000 97 per 1000 RR 1.98 646 +--- See above
loss of venous (54 to 174) (1.11 to (two studies) VERY LOW
access 3.55) Due to serious risk
of bias, very serious
inconsistency and
serious imprecision
However, this evidence was down-graded based on the risk Discussion

of bias and imprecision in the trials evaluated. The summary of the group’s recommendations empha-
sises the importance of avoiding VALI in patients with
ARDS, as all of the interventions with positive recom-
Grade recommendation statement mendations apart from maintaining a conservative fluid
We do not recommend the use of prone positioning for balance, arguably act through this process. Despite at
all patients with ARDS. We recommend the use of prone best moderate quality evidence by MA, we have strongly
positioning for at least 12 hours per day in patients with supported the use of low tidal volume and low airway
moderate/severe ARDS (P/F ratio<20 kPa: GRADE recom- pressure mechanical ventilation. This ventilation strategy
mendation: strongly in favour). is supported by results of the ARDS Network ARMA
study,87 data from studies whose primary outcome was
copyright.
Grade recommendation justification the prevention of ARDS and a large volume of evidence
Current evidence includes the possibility of substan- from preclinical and mechanistic studies. It is now so
tial patient benefit in terms of reduced mortality universally accepted that it is mandated for all patients
when combined with lung-protective ventilation and in clinical trials of ARDS. When applied to patients
when delivered for at least 12 hours to patients with with moderate/severe ARDS for at least 12 hours per
moderate/severe ARDS. Evidence for these findings day, prone positioning was also strongly recommended
was of moderate quality. The GDG noted the relative because the most recent studies focused enrolment on
improvements in study design over the time course of the most severe strata of patients with ARDS and involved
publication of all eight trials, such that the most recently a multimodal intervention comprising lung-protective
published focused enrolment on the most severe strata ventilation with prolonged prone positioning producing
of patients with ARDS, and involved a multimodal inter- highly favourable outcomes.129 By contrast, despite a
vention comprising lung-protective ventilation with strong theoretical rationale as a means of preventing
prolonged prone positioning producing highly favour- VALI, high frequency oscillatory ventilation was inef-
able outcomes.129 This observation provides the rationale fective or deleterious in two large studies leading to our
for the strong classification of recommendation. recommendation strongly against its use.
The possibility for substantial patient benefit must While broadly similar recommendations for the
be considered in the context of a significant risk of management of ARDS have been produced, many ques-
occurrence of adverse events including endotracheal tions remain. Fundamentally the parameters charac-
tube displacement, pressure sores and loss of venous terising optimal protective mechanical ventilation are
access, although the evidence to support these findings unknown, as are the optimal means of achieving them.
was either low or very low. However, the GDG felt that We have recommended targeting <6 mL/kg ideal body
these adverse events could be mitigated by ensuring that weight (IBW), but, based on the absence of evidence of
sufficient skilled personnel were in place to deliver and a safe tidal volume threshold on retrospective reanalysis
monitor the intervention. of the ARMA study130 and a dose-response effect seen
in observational studies,131 it would be reasonable to
recommend minimising tidal volume as far as possible.
Conclusion Similarly, analysing individual patient data from RCT
Summary concluded that driving pressure (plateau pressure minus
Table 12 outlines the GDG’s synthesis of data for the PEEP) was a better predictor of outcome than tidal
Management of ARDS from relevant clinical trials. volume or plateau pressure alone.132 Finally, there is no

Open access
Table 12 Summary of the FICM/ICS Guidelines for the management of ARDS in adult patients
GRADE
Topic recommendation Conditions
Tidal volume Strongly in favour Tidal volume <6 mL/kg ideal body weight; Plateau pressure < 30
cmH2O
Prone positioning Strongly in favour Proning for >12 hours per day
Patients with moderate/severe ARDS (P:F ratio < 20 kPa)
HFOV Strongly against
Conservative fluid management Weakly in favour
Higher PEEP Weakly in favour Patients with moderate or severe ARDS (PF ratio <27 kPa)
NMBA Weakly in favour Evidence only for cisatracurium besylate
Continuous 48 hours infusion
Patients with moderate/severe ARDS (<20 kPa)
ECMO Weakly in favour With lung-protective mechanical ventilation
Patients with severe ARDS, lung injury score >3 or pH <7.20 due to
uncompensated hypercapnoea
Inhaled vasodilators Weakly against Evidence only for inhaled nitric oxide
Corticosteroids Research recommendation
ECCO2R Research recommendation
ARDS, acute respiratory distress syndrome; ECCO2R, extracorporeal carbon dioxide removal; ECMO, extracorporeal membrane oxygenation; FICM,
Faculty of Intensive Care Medicine; HFOV, high frequency oscillation; ICS, Intensive Care Society; NMBA, neuromuscular blocking agents; PEEP,
peek end-expiratory pressure.
consensus regarding the means used to optimise PEEP of interventions has evolved rather than being formally
(oxygenation or various lung mechanical parameters) tested. For example, attempts have been made to test
or to manage the respiratory acidosis that commonly a so-called ‘open lung approach', by combining higher
accompanies protective ventilation. PEEP levels with low tidal volume ventilation both in early
copyright.
In certain details, recent guidelines have diverged. studies concentrating on low tidal volume ventilation,
We felt that the evidence supporting the role of recruit- in subsequent PEEP trials and more recently in studies
ment manoeuvres was so poor and the concept so ill-de- combining the use of recruitment manoeuvres and high
fined that we were unable to make a recommendation. levels of PEEP. The rationale for the open lung approach
By contrast, the American Thoracic Society/European is that increasing airway pressure will increase the volume
Society of Intensive Care Medicine/Society of Critical of ventilatable lung, thereby decreasing VALI and a large
Care Medicine group has given a conditional recommen- clinical trial was supported by encouraging pilot data.
dation, although with low-to-moderate confidence.5 Simi- This Alveolar Recruitment for Acute Respiratory Distress
larly, our group did not consider airway pressure release Syndrome Trial (ART) carried out in 1010 patients with
ventilation owing to the paucity of high quality, relevant severe ARDS surprisingly showed significantly higher
evidence, despite the knowledge that this ventilatory 6-month mortality (65.3% vs 59.9%) in the intervention
mode is widely used. Hopefully there will be sufficient group.133 These data demonstrate the enduring value of
evidence to justify including these interventions in the large well-conducted clinical trials of complex interven-
next version of the guidelines. tions in this challenging patient group.
We have synthesised available evidence with the clin-
ical practice of the GDG into a management algo-
rithm (figure 1). Hence, for a patient presenting with Unmet needs, research and future directions
for example severe ARDS, low tidal volume (<6 ml/kg We have made research recommendations for two inter-
IBW) and low plateau pressure (<30 cmH2O), mechan- ventions for adult patients with ARDS: corticosteroids and
ical ventilation using higher PEEP is recommended with ECCO2R. Two international studies are currently exam-
the addition of neuromuscular blockade for the first 48 ining the effects of ECCO2R combined with ultralow tidal
hours and prone positioning for at least 12 hours per volume ventilation (pRotective vEntilation with Veno-ve-
day. After initial resuscitation of the circulation, a neutral nouS Lung Assi (pRotective vEntilation With Veno-ve-
or, if tolerated, a negative fluid balance target should be nouS Lung assisT in Respiratory Failure (REST, Clinical-
set. Consideration of escalation to extracorporeal lung Trials.gov NCT02654327) and SUPERNOVA: A Strategy
support (ECMO or ECCO2R) is indicated by the failure of UltraProtective lung ventilation with Extracorporeal
to achieve adequate gas exchange using protective venti- CO2 Removal for New-Onset moderate to seVere ARDS,
latory settings as described above. To what extent is this whose pilot study has just been reported.
synthesis evidence-based? While the individual compo- There are no disease modifying, drug therapies for
nents are to an extent evidence-based, the combination ARDS. Drug development in this area is notoriously

Open access
difficult, partly because ARDS is not a disease but a minimise iatrogenic injury and the consequences of
syndrome describing acute respiratory failure occurring severe critical illness (ie, secondary and tertiary preven-
de novo as a result of a wide variety of conditions. One tion). We have combined these strategies with the
strategy designed to increase the likelihood of positive outcome of the analysis of evidence relating to the topics
clinical trials in ARDS is to select a less heterogeneous selected in figure 3.
patient population—a step on the road to a personalised
approach made at the expense of having a smaller pool
Primary prevention
of patients from which to recruit. Such splitting can be
A common theme of research into critical illness has been
envisaged on the basis of readily identifiable predisposing
the increasing appreciation of the contribution of iatro-
causes (eg, influenza pneumonia, transfusion-related
genic factors, most notably: fluid overload, VALI from
acute lung injury (TRALI) or systemic sepsis) or inherent
mechanical ventilation, transfusion of blood products
patient characteristics, such as alcoholism or the expres-
and hospital acquired infection.138 While it is sobering to
sion of particular single nucleotide polymorphisms
appreciate the negative role that healthcare systems have
known to be associated with a predisposition to ARDS.
played, it has at least indicated the potential to prevent
The ultimate aim is to identify subgroups, so-called endo-
ARDS through simple quality improvement interven-
types of ARDS that will predict a positive response to a
tions.139 140 Similarly, while causes of ARDS that act directly
certain class of therapy.134
on the lung, including pneumonia and gastric aspiration,
Current management of ARDS is hampered by failure to
are associated with a rapid progression to ARDS, indirect
diagnose the condition and to prevent iatrogenic harms.
causes typified by severe sepsis commonly evolve into
We need to heighten awareness of the diagnosis, partic-
ARDS as part of a multiorgan dysfunction syndrome over
ularly outside ICU, so that the opportunity to prevent
2–4 days.14
progression of the syndrome is not missed. Research into
Scoring systems have been developed to predict
prevention and treatment needs to be translated more
progression to ARDS both in patients at risk and those
effectively into the clinic. Biomarkers that confirmed the
with early lung injury. The Lung Injury Prediction Score
diagnosis highlighted patients with a poor prognosis and
(LIPS: table 13) is the product of a series of epidemiolog-
predicted that a positive response to a particular therapy
ical studies.141 142 LIPS was designed to identify a popu-
would be invaluable in research and clinical care. For
lation of patients at high risk of ARDS for prevention
example, a validated bedside biomarker of VALI would
copyright.
studies to be carried out by the National Institutes of
facilitate the fine tuning of mechanical ventilation and
Health’s Prevention and Early Treatment of Acute Lung
could guide related decisions during the recovery phase
Injury (PETAL) Network (http://petalnet.org/). LIPS-A
of ARDS, for example, assessing the risk-benefit relation-
was a large multicentre study to address the question
ship between allowing spontaneous ventilatory modes
of whether ARDS can be prevented with a drug, in this
with associated larger tidal volumes.
case aspirin, the latest in a succession of promising ther-
In order to discover effective drug therapies, continued
apeutics for ARDS, which was supported by a plethora
investment in human studies that aim to elucidate the
of positive preclinical data. Disappointingly, the study
pathogenesis of ARDS is essential to identify clinically
was negative and one contributing factor was that the
useful biomarkers and surrogate outcome measures.135 136
score threshold for study inclusion produced only half
These investigations need to be performed with a view to
the predicted number of ARDS cases, the study’s primary
designing a stepwise approach to testing novel therapeu-
outcome.143 This raises concerns about the ability of LIPS
tics in this particularly challenging patient group.137
to identify an enriched population of patients at risk for
Finally, standardisation of outcome measures will help
ARDS without the addition of factors such as biomarkers
in the conduct and comparison of clinical trials and such
that can predict deterioration from at risk, to mild, to
work is underway, for example, the Core Outcomes for
severe ARDS, and to death. Similarly, by characterising
Ventilation Trials: the COVenT Delphi study (COMET
patients early in their clinical course before they develop
registration: http://www.comet-initiative.org/studies/
ARDS, it has been possible to refine the parameters to
details/292). As reflected in the outcome prioritisation
the need for supplemental oxygen, an elevated respira-
exercise carried out by the GDG, there is an increasing
tory rate and bilateral infiltrates on the chest radiograph
emphasis on the health of survivors of critical illness,
to identify patients with early acute lung injury (EALI).144
which mandates that clinical trials include long-term
Validation by means of a multicentre study prospec-
outcomes and economic analysis that will inform the soci-
tively evaluating the positive predictive value of a score
etal impact of intensive care medicine.
comprising these variables would be required to generate
a EALI score that could have a similar role to LIPS in
future trials.
Management of ARDS in practice
Management
The essence of management of ARDS consists of opti- Secondary and tertiary prevention
mising the diagnosis and treatment of underlying condi- Transfusion of blood products has been associated
tions, and the deployment of supportive measures that with the incidence of ARDS, nosocomial infection and

Open access
copyright.
Figure 3 Analysis of evidence relating to the topics selected in this figure. ARDS, acute respiratory distress syndrome; CPAP,
continuous positive airway pressure; ECMO, extracorporeal membrane oxygenation; PEEP, positive end-expiratory pressure.
mortality in critical illness. TRALI is defined as the products containing the most plasma confer the highest
onset of ARDS within 6 hours of the transfusion of any risk and the exclusion of female donors of products with
blood product in the absence of another risk factor.145 high plasma volume has resulted in a decrease of roughly
The most important mechanism of injury appears to be two-thirds in the incidence of TRALI. Transfusion of
the interaction of preformed antibodies in the product packed red cells using a threshold of 7 was non-inferior
with the host pulmonary vascular endothelium. Hence, to a threshold of 9 g/dL and corresponding protocols

Open access
Table 13 The lung injury prediction score
LIPS
Predisposing conditions Score Examples
Shock 2 (1) Patient with history of alcohol abuse with septic shock from
Aspiration 2 pneumonia requiring FiO2>0.35
Emergency room: sepsis+shock+pneumonia+alcohol
Sepsis 1 abuse+FiO2>0.35
Pneumonia 1.5 1+2+1.5+1+2=7.5
(2) Motor vehicle accident with traumatic brain injury, lung
High-risk surgery* contusion and shock requiring FiO2>0.35
Orthopaedic spine 1 Traumatic brain injury+lung contusion+shock+FiO2>0.35
2+1.5+2+2=7.5
Acute abdomen 2
(3) Patient with history of diabetes mellitus and urosepsis with
Cardiac 2.5 shock sepsis+shock+diabetes
Aortic vascular 3.5 1+2–1=2
High-risk trauma
Traumatic brain injury 2
Smoke inhalation 2
Near drowning 2
Lung contusion 1.5
Multiple fractures 1.5
Risk modifiers
Alcohol abuse 1
Obesity (BMI>30) 1
Hypoalbuminaemia 1
Chemotherapy 1
FiO2 >0.35 (>4 L/min) 2
copyright.
Tachypnoea (RR>30) 1.5
SpO2 <95% 1
Acidosis (pH<7.35) 1.5
Diabetes mellitus† -1
*Add 1.5 points in case of emergency surgery.

†Only in cases of sepsis.
BMI, body mass index; RR, respiratory rate; SpO2, oxygen saturation by pulse oximetry.
6
restricting unnecessary transfusion should be introduced Respiratory Medicine, King's College London, London, UK
7
locally and practices audited. Division of Infection,Immunity and Respiratory Medicine,NIHR Biomedical
Research Centre, University of Manchester, Manchester, Greater Manchester,
There is a lack of evidence-based practices that decrease UK
hospital acquired infection. An effective local antibi- 8
Intensive Care, Heath Hospital, Cardiff, UK
otic policy should aim to optimise antibiotic treatment 9
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
according to local surveillance data and to ensure rapid
de-escalation based on culture results. Recent evidence Contributors Each author contributed elements to the final text.
suggests that enteral nutrition is preferable to parenteral, Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-for-profit sectors.
and that underfeeding is less dangerous than overpro-
vision. Finally, active rehabilitation, specialist outpatient Competing interests Each author contributed elements to the final text.
follow-up and psychological support have been recom- Patient consent for publication Not required.
mended for all survivors of severe critical illness in order Provenance and peer review Not commissioned; internally peer reviewed.
to mitigate the associated neuropsychological effects and Data sharing statement All data relevant to the study are included in the article
weakness.146 or uploaded as supplementary information.
Open access This is an open access article distributed in accordance with the
Author affiliations Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
1 permits others to distribute, remix, adapt, build upon this work non-commercially,
Peri-Operative Medicine, Barts Health NHS Trust, London, UK
2 and license their derivative works on different terms, provided the original work is
Wellcome-Wolfson Institute for Experimental Medicine, Queens University properly cited, appropriate credit is given, any changes made indicated, and the
Belfast, Belfast, UK use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
3
Warwick Clinical Trials Unit, University of Warwick, Coventry, , UK
4
Critical Care, Saint Thomas' Hospital, London, UK
5
Academic Department of Critical Care, QueenAlexandra Hospital, Portsmouth
Hospitals NHS Trust, Portsmouth, UK

Open access
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Guidelines

To cite: Griffiths MJD, Abstract required of carers for these complex patients.

Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

2 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420 3

Table 1 Corticosteroids compared to placebo for ARDS

ARDS, acute respiratory distress syndrome; ICU, intensive care unit.

4 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420 5

ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation.

6 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

ECCO2R, extracorporeal carbon dioxide removal.

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Study identification Analysis of outcomes

8 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420 9

ARDS, acute respiratory distress syndrome; HFOV, high-frequency oscillatory ventilation.

10 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

A GRADE Summary of Findings table is shown below Length of stay

Analysis of outcomes Economic data

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Study identification ICU length of stay

12 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

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Study identification GRADE evidence table can be found as part of online

14 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420 15

reported a RR 0.90 (0.81 to 1), with evidence supporting

16 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

Study identification Economic data

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18 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

However, this evidence was down-graded based on the risk Discussion

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20 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

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22 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

*Add 1.5 points in case of emergency surgery.

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24 Griffiths MJD, et al. BMJ Open Resp Res 2019;6:e000420. doi:10.1136/bmjresp-2019-000420

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