Академический Документы
Профессиональный Документы
Культура Документы
Protected by copyright.
Guidelines
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
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
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
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
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
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
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
Analysis of outcomes
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:
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
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
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,
Table 3 ECCO2R compared to standard care for acute respiratory distress syndrome
Patient or population: adults with ARDS
Settings: intensive care
Intervention: ECCO2R
Comparison: standard care
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
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
Analysis of outcomes
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
AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; RRT, renal replacement therapy.
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
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.
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
Grade recommendation statement
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.
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).
Table 7 Lower tidal volume compared with higher tidal volume (at similar PEEP) for ARDS
Patient or population: adults with ARDS
Settings: intensive care
Intervention: lower tidal volume
Comparison: higher, conventional tidal volume
Illustrative comparative risks* (95% CI)
Control risk Intervention risk
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
Patient or population: adults with ARDS
Settings: intensive care
Intervention: lower tidal volume and higher PEEP (LV/PEEP)
Comparison: higher tidal volume and lower PEEP (HV/PEEP)
Illustrative comparative risks*
(95% CI)
Control risk Intervention risk
No. of
Low PEEP/ High PEEP/ Low Relative effect participants Quality of evidence
Outcomes HIGH TV TV (95% CI) (studies) (GRADE) Comments
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
Due to inconsistency
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
Due to inconsistency
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?
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.
ARDS, acute respiratory distress syndrome; ICU, intensive care unit; NMBA, neuromuscular blocking agents; RCT, randomised controlled trial.
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 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.
Grade recommendation statement
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
ARDS, acute respiratory distress syndrome; ICU, intensive care unit; PEEP, positive end-expiratory pressure.
Table 11 Prone positioning compared with standard care for ARDS
Illustrative comparative risks (95% CI)
Relative No. of
Control risk Intervention risk
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
Subgroup 479 per 1000 359 per 1000 RR 0.75 1006 +++- MODERATE See above
analysis (311 to 416) (0.65 to (five studies) Due to serious risk
Prone positioning 0.87) of bias
for more than 12
hours
Mortality
Subgroup 457 per 1000 471 per 1000 RR 1.03 1135 +++- MODERATE See above
analysis (416 to 535) (0.91 to (three studies) Due to serious risk
Prone positioning 1.17) of bias
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
Adverse events: 248 per 1000 218 per 1000 RR 0.88 1007 ++-- See above
ventilator- (176 to 270) (0.71 to (four studies) LOW
associated 1.09) Due to serious risk
pneumonia of bias and serious
imprecision
Adverse events: 375 per 1000 462 per 1000 RR 1.23 1095 ++-- See above
pressure sores (402 to 529) (1.07 to (two studies) LOW
1.41) Due to serious risk
of bias and serious
imprecision
Continued
Adverse events: 67 per 1000 58 per 1000 RR 0.87 1160 ++-- See above
pneumothorax (40 to 87) (0.59 to (four studies) LOW
1.30) Due to serious risk
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
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
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
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
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
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
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
Tachypnoea (RR>30) 1.5
SpO2 <95% 1
Acidosis (pH<7.35) 1.5
Diabetes mellitus† -1
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
Society of Critical Care Medicine (2006)]. Zhongguo Wei Zhong 68. Adhikari NKJ, Burns KEA, Friedrich JO, et al. Effect of nitric oxide
Bing Ji Jiu Yi Xue 2006;18:706–10. on oxygenation and mortality in acute lung injury: systematic review
48. Uhlig C, Silva PL, Deckert S, et al. Albumin versus crystalloid and meta-analysis. BMJ 2007;334.
solutions in patients with the acute respiratory distress syndrome: a 69. Ruan S-Y, Huang T-M, Wu H-Y, et al. Inhaled nitric oxide therapy
systematic review and meta-analysis. Crit Care 2014;18. and risk of renal dysfunction: a systematic review and meta-
49. Martin GS, Moss M, Wheeler AP, et al. A randomized, controlled analysis of randomized trials. Crit Care 2015;19.
trial of furosemide with or without albumin in hypoproteinemic 70. Adhikari NKJ, Dellinger RP, Lundin S, et al. Inhaled nitric oxide
patients with acute lung injury*. Critical Care Medicine does not reduce mortality in patients with acute respiratory distress
2005;33:1681–7. syndrome regardless of severity: systematic review and meta-
50. Martin GS, Mangialardi RJ, Wheeler AP, et al. Albumin and analysis. Crit Care Med 2014;42:404–12.
furosemide therapy in hypoproteinemic patients with acute lung 71. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled
injury*. Crit Care Med 2002;30:2175–82. nitric oxide in patients with acute respiratory distress syndrome:
51. National Heart L, Wiedemann HP, Blood Institute Acute Respiratory results of a randomized phase II trial. inhaled nitric oxide in ARDS
Distress Syndrome Clinical Trials N,. Et al. Comparison of two Study Group. Crit Care Med 1998;26:15–23.
fluid-management strategies in acute lung injury. N Engl J Med 72. Gerlach H, Keh D, Semmerow A, et al. Dose-response
2006;354:2564–75. characteristics during long-term inhalation of nitric oxide in patients
52. Hu W, Lin C-W, Liu B-W, et al. Extravascular lung water and with severe acute respiratory distress syndrome: a prospective,
pulmonary arterial wedge pressure for fluid management in patients randomized, controlled study. Am J Respir Crit Care Med
with acute respiratory distress syndrome. Multidiscip Respir Med 2003;167:1008–15.
2014;9. 73. Lundin S, Mang H, Smithies M, et al. Inhalation of nitric oxide in
53. Wang LL, LV M X. Effect of different liquid strategies on the acute lung injury: results of a European Multicentre study. The
prognosis of acute respiratory distresssyndrome. Journal of the European Study Group of inhaled nitric oxide. Intensive Care Med
Dalian Nedical University 2014;36:140–3. 1999;25:911–9.
54. Liu KD, Thompson BT, Ancukiewicz M, et al. Acute kidney injury 74. Mehta S, MacDonald R, Hallett DC, et al. Acute oxygenation
in patients with acute lung injury: impact of fluid accumulation on response to inhaled nitric oxide when combined with high-
classification of acute kidney injury and associated outcomes. Crit frequency oscillatory ventilation in adults with acute respiratory
Care Med 2011;39:2665–71. distress syndrome*. Crit Care Med 2003;31:383–9.
55. Mikkelsen ME, Christie JD, Lanken PN, et al. The adult respiratory 75. Michael JR, Barton RG, Saffle JR, et al. Inhaled nitric oxide versus
distress syndrome cognitive outcomes study: long-term conventional therapy: effect on oxygenation in ARDS. Am J Respir
neuropsychological function in survivors of acute lung injury. Am J Crit Care Med 1998;157:1372–80.
Respir Crit Care Med 2012;185:1307–15. 76. Park KJ, Lee YJ, Oh YJ, et al. Combined effects of inhaled nitric
56. Bollen CW, van Well GTJ, Sherry T, et al. High frequency oscillatory oxide and A recruitment maneuver in patients with acute respiratory
ventilation compared with conventional mechanical ventilation in distress syndrome. Yonsei Med J 2003;44:219–26.
adult respiratory distress syndrome: a randomized controlled trial 77. Payen DM. Inhaled nitric oxide and acute lung injury. Clin Chest
[ISRCTN24242669]. Crit Care 2005;9:R430–R9. Med 2000;21:519–29.
57. Demory D, Michelet P, Arnal J-M, et al. High-frequency oscillatory 78. Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled
ventilation following prone positioning prevents a further nitric oxide in patients with acute lung injury: a randomized
impairment in oxygenation. Crit Care Med 2007;35:106–11. controlled trial. JAMA 2004;291:1603–9.
58. Derdak S, Mehta S, Stewart TE, et al. High-frequency oscillatory 79. Troncy E, Collet JP, Shapiro S, et al. Inhaled nitric oxide in acute
ventilation for acute respiratory distress syndrome in adults: respiratory distress syndrome: a pilot randomized controlled study.
a randomized, controlled trial. Am J Respir Crit Care Med Am J Respir Crit Care Med 1998;157:1483–8.
2002;166:801–8. 80. Eichacker PQ, Gerstenberger EP, Banks SM, et al. Meta-analysis
59. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency of acute lung injury and acute respiratory distress syndrome
oscillation in early acute respiratory distress syndrome. N Engl J trials testing low tidal volumes. Am J Respir Crit Care Med
Med 2013;368:795–805. 2002;166:1510–4.
60. Shah SB, Jackson SK, Findlay GP, et al. Prospective study 81. Petrucci N, Iacovelli W. Ventilation with smaller tidal volumes: a
comparing high frequency oscillatory ventilation (HFOV) versus quantitative systematic review of randomized controlled trials.
conventional (CMV) in patients with acute respiratory distress Anesth Analg 2004;99:193–200.
syndrome (ARDS) [Abstract]. American Thoracic Society 2005 82. Qin ZQ. Wang C. A meta-analysis of clinical studies of low volume
International Conference; May 20-25. San Diego, California, ventilation in acute respiratory distress syndrome. [Chinese].
2005D15 . Zhonghua yi xue za zhi 2003;83:224–7.
61. Young NH, Andrews PJD. High-frequency oscillation as a 83. Fuller BM, Mohr NM, Drewry AM, et al. Lower tidal volume at
rescue strategy for brain-injured adult patients with acute lung initiation of mechanical ventilation may reduce progression to
injury and acute respiratory distress syndrome. Neurocrit Care acute respiratory distress syndrome: a systematic review. Crit Care
2011;15:623–33. 2013;17.
62. Mentzelopoulos SD, Malachias S, Zintzaras E, et al. Intermittent 84. Burns KEA, Adhikari NKJ, Slutsky AS, et al. Pressure and volume
recruitment with high-frequency oscillation/tracheal gas limited ventilation for the ventilatory management of patients with
insufflation in acute respiratory distress syndrome. Eur Respir J acute lung injury: a systematic review and meta-analysis. PLoS
2012;39:635–47. One 2011;6.
63. Mentzelopoulos SD, Roussos C, Koutsoukou A, et al. Acute effects 85. Petrucci N, De Feo C, Cochrane Emergency and Critical Care
of combined high-frequency oscillation and tracheal gas insufflation Group. Lung protective ventilation strategy for the acute respiratory
in severe acute respiratory distress syndrome. Crit Care Med distress syndrome. Cochrane Database Syst Rev 2013;338.
2007;35:1500–8. 86. Putensen C, Theuerkauf N, Zinserling J, et al. Meta-analysis:
64. XL G, GN W, Yao YW, et al. Is high-frequency oscillatory ventilation ventilation strategies and outcomes of the acute respiratory
more effective and safer than conventional protective ventilation distress syndrome and acute lung injury.[Erratum appears in
in adult acute respiratory distress syndrome patients? A meta- Ann Intern Med. 2009 Dec 15;151(12):897]. Ann Intern Med
analysis of randomized controlled trials (provisional Abstract). 2009;151:566–76.
Database of Abstracts of Reviews of Effects 2014. 87. Brower RG, Matthay MA, Morris A, et al. Ventilation with lower tidal
65. Huang CT, Lin HH, et al, Efficacy and adverse events of high volumes as compared with traditional tidal volumes for acute lung
frequency oscillatory ventilation in adult patients with acute injury and the acute respiratory distress syndrome. N Engl J Med
respiratory distress syndrome: a meta-analysis (Provisional 2000;342:1301–8.
abstract). Database of Abstracts of Reviews of Effects 2014. 88. Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal Volume
66. Maitra S, Bhattacharjee S, Khanna P, et al. High-frequency Reduction for Prevention of Ventilator-induced Lung Injury in
ventilation does not provide mortality benefit in comparison with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med
conventional lung-protective ventilation in acute respiratory distress 1998;158:1831–8.
syndrome: a meta-analysis of the randomized controlled trials 89. Brower RG, Shanholtz CB, Fessler HE, et al. Prospective,
(provisional Abstract). Database of Abstracts of Reviews of Effects randomized, controlled clinical trial comparing traditional versus
2014. reduced tidal volume ventilation in acute respiratory distress
67. Afshari A, Brok J, Møller AM, et al. Aerosolized prostacyclin for syndrome patients. Crit Care Med 1999;27:1492–8.
acute lung injury (ali) and acute respiratory distress syndrome 90. Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a ventilation
(ARDS). Cochrane Database Syst Rev 2010;(8):CD007733. strategy to prevent barotrauma in patients at high risk for acute
respiratory distress syndrome. Pressure- and Volume-Limited 113. Alsaghir AH, Martin CM. Effect of prone positioning in patients with
Ventilation Strategy Group. N Engl J Med 1998;338:355–61. acute respiratory distress syndrome: a meta-analysis. Crit Care
91. Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume Med 2008;36:603–9.
reduction for prevention of ventilator-induced lung injury in acute 114. Ball C. Use of the prone position in the management of
respiratory distress syndrome. The Multicenter TRAIL group acute respiratory distress syndrome. Intensive Crit Care Nurs
on tidal volume reduction in ARDS. Am J Respir Crit Care Med 1999;15:192–203.
1998;158:1831–8. 115. Beitler JR, Shaefi S, Montesi SB, et al. Prone positioning reduces
92. Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective- mortality from acute respiratory distress syndrome in the low tidal
ventilation strategy on mortality in the acute respiratory distress volume era: a meta-analysis. Intensive Care Med 2014;40:332–41.
syndrome. N Engl J Med 1998;338:347–54. 116. Curley MA. Prone positioning of patients with acute respiratory
93. Villar J, Kacmarek RM, Pérez-Méndez L, et al. A high positive end- distress syndrome: a systematic review. Am J Crit Care
expiratory pressure, low tidal volume ventilatory strategy improves 1999;8:397–405.
outcome in persistent acute respiratory distress syndrome: a 117. Hu SL, He HL, Pan C, et al. The effect of prone positioning on
randomized, controlled trial. Crit Care Med 2006;34:1311–8. mortality in patients with acute respiratory distress syndrome: a
94. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J meta-analysis of randomized controlled trials. Crit Care 2014;18.
Med 2013;369:2126–36. 118. Kopterides P, Siempos II, Armaganidis A. Prone positioning in
95. Yang D, Grant MC, Stone A, et al. A meta-analysis of intraoperative hypoxemic respiratory failure: meta-analysis of randomized
ventilation strategies to prevent pulmonary complications: is low controlled trials. J Crit Care 2009;24:89–100.
tidal volume alone sufficient to protect healthy lungs? Ann Surg 119. Lee JM, Bae W, Lee YJ, et al. The efficacy and safety of prone
2016;263:881–7. positional ventilation in acute respiratory distress syndrome:
96. Alhazzani W, Alshahrani M, Jaeschke R, et al. Neuromuscular updated study-level meta-analysis of 11 randomized controlled
blocking agents in acute respiratory distress syndrome: a trials. Crit Care Med 2014;42:1252–62.
systematic review and meta-analysis of randomized controlled 120. Park SY, Kim HJ, Yoo KH, et al. The efficacy and safety of prone
trials. Crit Care 2013;17. positioning in adults patients with acute respiratory distress
97. Neto AS, Pereira VGM, Espósito DC, et al. Neuromuscular blocking syndrome: a meta-analysis of randomized controlled trials. J
agents in patients with acute respiratory distress syndrome: a Thorac Dis 2015;7:356–67.
summary of the current evidence from three randomized controlled 121. Sud S, Friedrich JO, Adhikari NKJ, et al. Effect of prone positioning
trials. Ann Intensive Care 2012;2. during mechanical ventilation on mortality among patients with
98. Tonelli AR, Zein J, Adams J, et al. Effects of interventions on acute respiratory distress syndrome: a systematic review and meta-
survival in acute respiratory distress syndrome: an umbrella review analysis. CMAJ 2014;186:E381–E390.
of 159 published randomized trials and 29 meta-analyses. Intensive 122. —————–, —————–, Taccone P, et al. Prone ventilation
Care Med 2014;40:769–87. reduces mortality in patients with acute respiratory failure and
99. Duggal A, Ganapathy A, Ratnapalan M, et al. Pharmacological severe hypoxemia: systematic review and meta-analysis. Intensive
treatments for acute respiratory distress syndrome: systematic Care Med 2010;36:585–99.
review. Minerva Anestesiol 2015;81:567–88. 123. Tiruvoipati R, Bangash M, Manktelow B, et al. Efficacy of prone
100. Gainnier M, Roch A, Forel J-M, et al. Effect of neuromuscular ventilation in adult patients with acute respiratory failure: a meta-
blocking agents on gas exchange in patients presenting with acute analysis. J Crit Care 2008;23:101–10.
respiratory distress syndrome. Crit Care Med 2004;32:113–9. 124. Chan M-C, Hsu J-Y, Liu H-H, et al. Effects of prone position on
101. Papazian L, Forel J-M, Gacouin A, et al. Neuromuscular blockers inflammatory markers in patients with ARDS due to community-
in early acute respiratory distress syndrome. N Engl J Med acquired pneumonia. J Formos Med Assoc 2007;106:708–16.
2010;363:1107–16. 125. Guerin C, Gaillard S, Lemasson S, et al. Effects of systematic prone
102. Forel J-M, Roch A, Marin V, et al. Neuromuscular blocking agents positioning in hypoxemic acute respiratory failure: a randomized
decrease inflammatory response in patients presenting with acute controlled trial. JAMA 2004;292:2379–87.
respiratory distress syndrome. Crit Care Med 2006;34:2749–57. 126. Mancebo J, Fernández R, Blanch L, et al. A multicenter trial of
103. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower prolonged prone ventilation in severe acute respiratory distress
positive end-expiratory pressures in patients with the acute syndrome. Am J Respir Crit Care Med 2006;173:1233–9.
respiratory distress syndrome. N Engl J Med 2004;351:327–36. 127. Taccone P, Pesenti A, Latini R, et al. Prone positioning in patients
104. Mercat A, Richard J-CM, Vielle B, et al. Positive end-expiratory with moderate and severe acute respiratory distress syndrome: a
pressure setting in adults with acute lung injury and acute randomized controlled trial. JAMA 2009;302:1977–84.
respiratory distress syndrome: a randomized controlled trial. JAMA 128. Higgins JPTG S. Cochrane Handbook for systematic reviews of
2008;299:646–55. interventions. The Cochrane Collaboration 2011.
105. Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy 129. Guérin C, Reignier J, Richard J-C, et al. Prone positioning in severe
using low tidal volumes, recruitment maneuvers, and high acute respiratory distress syndrome. N Engl J Med Overseas Ed
positive end-expiratory pressure for acute lung injury and acute 2013;368:2159–68.
respiratory distress syndrome: a randomized controlled trial. JAMA 130. Hager DN, Krishnan JA, Hayden DL, et al. Tidal volume reduction in
2008;299:637–45. patients with acute lung injury when plateau pressures are not high.
106. Talmor D, Sarge T, Malhotra A, et al. Mechanical ventilation Am J Respir Crit Care Med 2005;172:1241–5.
guided by esophageal pressure in acute lung injury. N Engl J Med 131. Needham DM, Colantuoni E, Mendez-Tellez PA, et al. Lung
2008;359:2095–104. protective mechanical ventilation and two year survival in
107. Huh JW, Jung H, Choi HS, et al. Efficacy of positive end-expiratory patients with acute lung injury: prospective cohort study. BMJ
pressure titration after the alveolar recruitment manoeuvre in 2012;344:e2124.
patients with acute respiratory distress syndrome. Crit Care 132. Amato MBP, Meade MO, Slutsky AS, et al. Driving pressure and
2009;13. survival in the acute respiratory distress syndrome. N Engl J Med
108. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end- 2015;372:747–55.
expiratory pressure in patients with acute lung injury and acute 133. Cavalcanti AB, Suzumura Érica Aranha, Laranjeira LN, et al.
respiratory distress syndrome: systematic review and meta- Effect of lung recruitment and titrated positive end-expiratory
analysis. JAMA 2010;303:865–73. pressure (PEEP) vs low PEEP on mortality in patients with acute
109. Oba Y, Thameem DM, Zaza T. High levels of PEEP may improve respiratory distress syndrome: a randomized clinical trial. JAMA
survival in acute respiratory distress syndrome: a meta-analysis. 2017;318:1335–45.
Respir Med 2009;103:1174–81. 134. Prescott HC, Calfee CS, Thompson BT, et al. Toward smarter
110. Santa Cruz R, Rojas JI, Nervi R, et al. High versus low positive lumping and smarter splitting: rethinking strategies for sepsis and
end-expiratory pressure (PEEP) levels for mechanically ventilated acute respiratory distress syndrome clinical trial design. Am J
adult patients with acute lung injury and acute respiratory distress Respir Crit Care Med 2016;194:147–55.
syndrome. Cochrane Database Syst Rev 2013;(6):CD009098. 135. Proudfoot AG, Hind M, Griffiths MJD. Biomarkers of acute lung
111. Abroug F, Ouanes-Besbes L, Dachraoui F, et al. An updated study- injury: worth their salt? BMC Med 2011;9.
level meta-analysis of randomised controlled trials on proning in 136. —————–, McAuley DF, Griffiths MJD, et al. Human models of
ARDS and acute lung injury. Crit Care 2011;15. acute lung injury. Dis Model Mech 2011;4:145–53.
112. —————–, —————–, Elatrous S, et al. The effect of prone 137. McAuley DF, O'kane C, Griffiths MJD. A stepwise approach
positioning in acute respiratory distress syndrome or acute lung to justify phase III randomized clinical trials and enhance
injury: a meta-analysis. areas of uncertainty and recommendations the likelihood of a positive result. Crit Care Med 2010;38(10
for research. Intensive Care Med 2008;34:1002–11. Suppl):S523–S527.
138. Salman D, Finney SJ, Griffiths MJD. Strategies to reduce ventilator- 142. Trillo-Alvarez C, Cartin-Ceba R, Kor DJ, et al. Acute lung injury
associated lung injury (VALI). Burns 2013;39:200–11. prediction score: derivation and validation in a population-based
139. Herasevich V, Tsapenko M, Kojicic M, et al. Limiting ventilator- sample. Eur Respir J 2011;37:604–9.
induced lung injury through individual electronic medical record 143. Kor DJ, Carter RE, Park PK, et al. Effect of aspirin on development
surveillance. Crit Care Med 2011;39:34–9. of ARDS in at-risk patients presenting to the emergency
140. Pickering BW, Litell JM, Herasevich V, et al. Clinical review: department: the LIPS-A randomized clinical trial. JAMA
the hospital of the future - building intelligent environments 2016;315:2406–14.
to facilitate safe and effective acute care delivery. Crit Care 144. Rackley CR, Levitt JE, Zhuo H, et al. Clinical evidence of early
2012;16. acute lung injury often precedes the diagnosis of Ali. J Intensive
141. Gajic O, Dabbagh O, Park PK, et al. Early identification of patients Care Med 2013;28:241–6.
at risk of acute lung injury: evaluation of lung injury prediction 145. Vlaar APJ, Juffermans NP. Transfusion-related acute lung injury: a
score in a multicenter cohort study. Am J Respir Crit Care Med clinical review. Lancet 2013;382:984–94.
2011;183:462–70. 146. NICE. Rehabilitation after critical illness. London: NICE, 2009.