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AMERICAN THORACIC SOCIETY

DOCUMENTS

An Ofcial American Thoracic Society/European Society of Intensive


Care Medicine/Society of Critical Care Medicine Clinical Practice
Guideline: Mechanical Ventilation in Adult Patients with Acute
Respiratory Distress Syndrome
Eddy Fan, Lorenzo Del Sorbo, Ewan C. Goligher, Carol L. Hodgson, Laveena Munshi, Allan J. Walkey,
Neill K. J. Adhikari, Marcelo B. P. Amato, Richard Branson, Roy G. Brower, Niall D. Ferguson, Ognjen Gajic,
Luciano Gattinoni, Dean Hess, Jordi Mancebo, Maureen O. Meade, Daniel F. McAuley, Antonio Pesenti,
V. Marco Ranieri, Gordon D. Rubenfeld, Eileen Rubin, Maureen Seckel, Arthur S. Slutsky, Daniel Talmor,
B. Taylor Thompson, Hannah Wunsch, Elizabeth Uleryk, Jan Brozek, and Laurent J. Brochard; on behalf of the
American Thoracic Society, European Society of Intensive Care Medicine, and Society of Critical Care Medicine
THIS OFFICIAL CLINICAL PRACTICE GUIDELINE OF THE AMERICAN THORACIC SOCIETY (ATS), EUROPEAN SOCIETY OF INTENSIVE CARE MEDICINE (ESICM), AND
SOCIETY OF CRITICAL CARE MEDICINE (SCCM) WAS APPROVED BY THE ATS, ESICM, AND SCCM, MARCH 2017

Background: This document provides evidence-based than 12 h/d (moderate condence in effect estimates). For patients with
clinical practice guidelines on the use of mechanical ventilation moderate or severe ARDS, the recommendation is strong against routine
in adult patients with acute respiratory distress syndrome (ARDS). use of high-frequency oscillatory ventilation (high condence in effect
estimates) and conditional for higher positive end-expiratory pressure
Methods: A multidisciplinary panel conducted systematic reviews (moderate condence in effect estimates) and recruitment maneuvers
and metaanalyses of the relevant research and applied Grading of (low condence in effect estimates). Additional evidence is necessary to
Recommendations, Assessment, Development, and Evaluation make a denitive recommendation for or against the use of
methodology for clinical recommendations. extracorporeal membrane oxygenation in patients with severe ARDS.
Results: For all patients with ARDS, the recommendation is strong for Conclusions: The panel formulated and provided the rationale for
mechanical ventilation using lower tidal volumes (48 ml/kg predicted recommendations on selected ventilatory interventions for adult
body weight) and lower inspiratory pressures (plateau pressure , 30 cm patients with ARDS. Clinicians managing patients with ARDS should
H2O) (moderate condence in effect estimates). For patients with severe personalize decisions for their patients, particularly regarding the
ARDS, the recommendation is strong for prone positioning for more conditional recommendations in this guideline.

Contents Manuscript Preparation Question 3: Should Patients with


Overview Recommendations for Specic ARDS Receive High-Frequency
Introduction Treatment Questions Oscillatory Ventilation?
Methods Question 1: Should Patients Question 4: Should Patients with
Committee Composition with ARDS Receive ARDS Receive Higher, as
Condentiality Agreement and Mechanical Ventilation Using Compared with Lower, PEEP?
Conict-of-Interest Management LTVs and Inspiratory Question 5: Should Patients with
Meetings Pressures? ARDS Receive RMs?
Formulating Clinical Questions Question 2: Should Patients Question 6: Should Patients with
Literature Search with ARDS Receive Prone ARDS Receive Extracorporeal
Evidence Review and Positioning? Membrane Oxygenation?
Development of Clinical Conclusions
Recommendations

Correspondence and requests for reprints should be addressed to Eddy Fan, M.D., Ph.D., Toronto General Hospital, 585 University Avenue, PMB 11-123,
Toronto, Ontario, M5G 2N2 Canada. E-mail: eddy.fan@uhn.ca
Am J Respir Crit Care Med Vol 195, Iss 9, pp 12531263, May 1, 2017
Copyright 2017 by the American Thoracic Society
DOI: 10.1164/rccm.201703-0548ST
Internet address: www.atsjournals.org

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Overview 4. Additional evidence is necessary to as an ARDS survivor (E.R.). On the basis of


make a denitive recommendation for interest and expertise, panel members were
The purpose of this guideline is to analyze or against the use of extracorporeal primarily assigned to one of three
evidence on the use of ventilatory strategies membrane oxygenation in patients with Recommendation subcommittees, each
and associated cointerventions in adult severe ARDS. chaired by a senior member. An additional
patients with acute respiratory distress Methodology subcommittee included a
Questions regarding some modes of
syndrome (ARDS) and to provide chair and two experts in systematic review
mechanical ventilation (e.g., airway pressure
treatment recommendations on the basis and guideline methods as well as a medical
release ventilation) and complementary
of these interventions. For each librarian (E.U.). Each subcommittee
pharmacologic interventions (e.g.,
recommendation, it is important to included at least one senior investigator to
neuromuscular blockade) were not
consider the quality of the evidence reviews provide oversight and at least one junior
addressed because of resource constraints.
and patient values and preferences before investigator to aid guideline development as
These questions are deferred to a future
applying these recommendations well as to gain valuable clinical, research,
version of the guideline.
to specic clinical situations or and methodological experience from leaders
policy decisions. No guideline or in the eld. The committee was cochaired by
recommendations can take into account all E.F. and L.J.B. Committee members
the compelling and unique clinical features Introduction represented the American Thoracic Society
of individual patients, and therefore (ATS), European Society of Intensive Care
clinicians, patients, policy makers, and ARDS is a life-threatening form of Medicine, and Society of Critical Care
other stakeholders should not regard these respiratory failure characterized by Medicine.
recommendations as mandatory. Finally, inammatory pulmonary edema resulting
although there may be good reasons to in severe hypoxemia (1). The severity of Condentiality Agreement and
extrapolate these treatments to other causes ARDS is classied according to the Conict-of-Interest Management
of acute hypoxemic respiratory failure or degree of hypoxemia (PaO2 /F IO 2 ratio), Committee members signed conict-of-
with mutually exclusive categories of interest statements. New or updated
to all mechanically ventilated patients, we
mild (Pa O 2/F I O2 , 201300), moderate conicts of interest were solicited by
exclusively reviewed data on patients with
(Pa O2 /F I O2 , 101200), and severe the Co-Chair (E.F.) at the start of each
ARDS, and recommendations therefore apply
(Pa O2 /F I O2 < 100) (2). ARDS is common, in-person meeting and teleconference.
only to this group of patients. A summary of
is associated with substantial morbidity, The views and interests of the ATS, European
our recommendations is as follows:
is frequently fatal, and represents an Society of Intensive Care Medicine, and
1. The recommendations for the following important public health problem (35). Society of Critical Care Medicine, or those of
interventions for the treatment of ARDS Despite decades of research, there are any commercial entity that provided funding
are strong: limited therapeutic options directed at the to these professional societies, had no
a. Mechanical ventilation using lower underlying pathological processes (6), and inuence on the topics discussed and
tidal volumes (48 ml/kg predicted supportive care with mechanical ventilation recommendations made.
body weight) and lower inspiratory remains the cornerstone of patient
pressures (plateau pressure , 30 cm management (7). With the understanding Meetings
H2O) (moderate condence in effect that mechanical ventilation itself can cause At a face-to-face meeting at the 2013 ATS
estimates) and potentiate lung injury, research has International Conference in Philadelphia,
b. Prone positioning for more than focused on ventilatory strategies and Pennsylvania, the panel discussed the scope
12 h/d in severe ARDS (moderate adjunctive measures aimed at mitigating this and objectives of the project and identied
condence in effect estimates) so-called ventilator-induced lung injury the specic clinical questions to be
2. The recommendation against the (VILI) (8). Importantly, ARDS appears to be addressed. An ATS methodologist (J.B.)
following intervention for the treatment underrecognized by clinicians, and evidence- presented an overview of the Grading of
of ARDS is strong: based interventions are underused (5). Thus, Recommendations, Assessment,
a. Routine use of high-frequency there is the potential for improved outcomes Development, and Evaluation (GRADE)
oscillatory ventilation in patients in patients with ARDS through enhanced process for guideline development to the
with moderate or severe ARDS (high uptake and implementation of evidence- panel. At the 2014 International
condence in effect estimates) based interventions. Symposium on Intensive Care and
3. The recommendation for the following Emergency Medicine in Brussels, Belgium,
interventions for the treatment of ARDS the panel studied preliminary results.
is conditional: Methods Finally, at the 2014 ATS International
a. Higher positive end-expiratory Conference in San Diego, California, the
pressure in patients with moderate or Committee Composition panel reviewed the ndings from the
severe ARDS (moderate condence We convened an interprofessional panel evidence summaries and drafted initial
in effect estimates) with a broad sample of clinical recommendations. Conference calls and
b. Recruitment maneuvers in patients epidemiologists, clinical trialists, e-mail correspondence were used to
with moderate or severe ARDS (low physiologists, and methodologists from discuss specic issues requiring input
condence in effect estimates) different disciplines and jurisdictions as well from other panel members, including

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updated literature searches and Evidence summaries for each question strength were decided by consensus.
evidence synthesis, nalizing the were prepared by the Working Group (E.F., In deliberating the strength of the
recommendations, and responding to A.J.W., E.C.G., C.L.H., L.M., L.D.S., M.O.M., recommendations, the committee weighed
peer review. N.K.J.A., H.W., and E.U.), following the the GRADE evidence proles and additional
GRADE approach (18) and using the evidence, including published study-level and
Formulating Clinical Questions GRADEpro Guideline Development Tool individual patient data metaanalyses, as well
The panel agreed on six specic questions online software (available at www. as pertinent physiological studies, to reach
pertinent to the ventilatory management of guidelinedevelopment.org). All panel our nal recommendations. Ultimately,
critically ill adults with ARDS. The panel members reviewed the summaries of guideline panels must use judgment in
identied outcomes of interest for each evidence, and corrections were made when integrating these factors to make a strong
question a priori and rated their relative appropriate. or conditional recommendation for or
importance (from the perspective of a The Working Group pooled results against an intervention. The committee
patient with ARDS) from not important from randomized trials with comparable agreed on the nal wording and further
to critical as per the GRADE framework (9). patients, intervention, and outcomes. In qualications of recommendations (e.g.,
An example of a critical outcome is some randomized controlled trials (RCTs), subgroup considerations, justications,
mortality. Ranking outcomes by their multiple ventilatory interventions were implementation considerations).
relative importance focuses attention on bundled together in the experimental group Recommendations are either strong
those that are most relevant to patients and (e.g., lower tidal volume [LTV] ventilation, or conditional according to the GRADE
helps to address potential disagreements in higher positive end-expiratory pressure approach (20). We used the GRADE
decision-making. [PEEP], recruitment maneuvers [RMs]). We phrases we recommend for strong
addressed this by limiting our primary recommendations and we suggest for
analyses for each PICO (Population, conditional recommendations.
Literature Search Intervention, Comparator, and Outcome) Recommendations of similar strength
A medical librarian (E.U.) helped to question to RCTs without important should not be interpreted as equivalent
develop a search strategy for each of the cointerventions. All metaanalyses were recommendations; instead, each
guideline questions, using controlled performed using random-effects models in recommendations strength is the net result
vocabulary terms and text words to RevMan 5.2 (Cochrane Collaboration, of multiple factors described earlier. As a
update existing systematic reviews Oxford, UK). Binary outcomes are result, there may be different reasons that
(1015). We evaluated existing presented as risk ratios and continuous two recommendations are rated with the
systematic reviews using the AMSTAR (A outcomes as weighted mean differences, same strength (for example, one may be
Measurement Tool to Assess Systematic both with 95% condence intervals (CIs). conditional because it is based on very low
Reviews) checklist (16). We searched All data fullling the a priori inclusion condence in the effect estimates, whereas
MEDLINE, EMBASE, Cochrane Registry criteria were included. Pooled analyses another could be conditional because it is
of Controlled Trials, Database of presented in this document may differ from unclear that potential benets outweigh the
Abstracts of Reviews of Effects (OvidSP), other published metaanalyses due to risks for every patient).
CINAHL (EBSCOHost), and Web of Science differences in study selection criteria. The
(Thomson Reuters) from the date of the last condence in effect estimates for each Manuscript Preparation
systematic review to August 2016, without outcome of interest was assessed using the The writing committee (E.F., L.D.S., E.C.G.,
language restrictions. Panel members were GRADE approach (19). Randomized trials C.L.H., L.M., N.K.J.A., and A.J.W.) drafted
also asked to highlight any additional studies begin as high-quality evidence and can be the guideline document for subsequent
not identied by the search. rated down on the basis of risk of bias, electronic review by the entire panel. The
inconsistency, indirectness, imprecision, or entire panel had the opportunity to correct
Evidence Review and Development of publication bias. The quality can be rated factual or interpretive errors. The nal
Clinical Recommendations up on the basis of large effect size and approved version was submitted to each
Two independent reviewers (A.J.W., E.C.G., doseresponse relationship. The overall cosponsoring professional society for review.
C.L.H., L.M., and L.D.S.) screened titles and condence in effect estimates for each
abstracts to identify randomized trials or outcome was categorized as high, moderate,
systematic reviews for each full review; they low, or very low. Recommendations for
also evaluated the full text of articles deemed The panel developed recommendations Specic Treatment
potentially relevant by any reviewer. on the basis of the GRADE evidence proles Questions
Disagreements were resolved by consensus. for each recommendation. The panel used the
Data were abstracted in duplicate, using GRADE decision framework to discuss and Question 1: Should Patients with
customized and pretested data abstraction evaluate each recommendation on the basis ARDS Receive Mechanical
forms. We used the Cochrane Collaboration of: the quality of evidence, the balance of Ventilation Using LTVs and Inspiratory
risk of bias instrument to assess random desirable and undesirable consequences of an Pressures?
sequence generation, allocation intervention, assumptions about values and
concealment, blinding of personnel, preferences of patients, acceptability of the Background. Supportive care with
blinding of outcome assessment, incomplete intervention to stakeholders, and clinical mechanical ventilation remains the
outcome data, and selective reporting (17). feasibility. All recommendations and their cornerstone of ARDS management.

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However, mechanical ventilation itself can inspiratory pressures (plateau reductions in tidal volume (for example,
cause and potentiate lung injury and may pressure , 30 cm H2O) (strong targets lower than 6 ml/kg PBW or lower
contribute to nonpulmonary organ failure recommendation, moderate condence in limits , 4 ml/kg PBW) or inspiratory
and mortality in patients with ARDS. This effect estimates). plateau pressure are associated with
insight led to the design and evaluation of Justication and implementation greater improvements in patient-
ventilatory strategies aimed at mitigating considerations. Although our primary important outcomes (30, 36). Finally, a
VILI. analysis showed no signicant difference recent observational study based on
Summary of the evidence. Mechanical in mortality, the boundary of the CI individual patient data from multiple
ventilation strategies that limit tidal volumes consistent with the largest plausible effect RCTs demonstrated that driving pressure
(48 ml/kg predicted body weight [PBW]: (29) suggests that LTV might reduce the (DP = plateau pressure PEEP) is a better
males = 50 1 0.91[height (cm)2152.4] kg relative risk of death by as much as 30%. predictor of outcome in ARDS than
and females = 45.5 1 0.91[height (cm)2 Furthermore, secondary analyses that either tidal volume or plateau pressure
152.4] kg) and inspiratory pressures included meta-regression and a (37). Future studies are needed to
(plateau pressure , 30 cm H2O, dened as sensitivity analysis including all trials evaluate whether ventilatory strategies
the pressure obtained after a 0.5-s (nine studies, 1,629 patients) supported a targeting reduced DP are more
inspiratory pause) have been compared clinically important benet to LTV. The efcacious than those targeting tidal
with traditional strategies (with tidal meta-regression of tidal volume gradient volume or plateau pressure.
volumes 1015 ml/kg PBW) in nine RCTs between experimental and control
including 1,629 patients (2128). Mean groups in each RCT versus mortality Question 2: Should Patients
(6SD) tidal volume in the LTV group was conrmed a doseresponse relationship with ARDS Receive Prone
6.8 6 1.2 ml/kg PBW, compared with to the effect of LTVs (30, 31). The initial Positioning?
11.4 6 1.1 ml/kg PBW in the traditional tidal volume should be set at 6 ml/kg
group. Our primary analysis excluded PBW and can be increased up to 8 ml/kg Background. Mechanical ventilation in
RCTs for which the LTV strategy was PBW if the patient is double triggering or the prone position has been evaluated as a
combined with the additional strategy of if inspiratory airway pressure decreases strategy to enhance oxygenation and lung
higher PEEP, but these trials were included below PEEP (25). The strong recruitment in ARDS. The mechanisms
in a stratied sensitivity analysis (21, 22). recommendation for LTVs therefore by which prone positioning may benet
Mortality was not signicantly different for comes from moderate condence in the patients with ARDS undergoing
patients receiving an LTV compared with magnitude of effects on highly valued mechanical ventilation include
traditional strategies (seven studies, 1,481 outcomes (e.g., mortality), supplemented improving ventilationperfusion
patients; risk ratio [RR], 0.87; 95% CI, by our secondary analyses, and moderate matching, increasing end-expiratory
0.701.08; moderate condence). There condence that undesirable outcomes are lung volume, and decreasing VILI by
were also no signicant differences in modest and their avoidance is not highly more uniform distribution of tidal
barotrauma (three studies, 1,029 patients; valued. volume through lung recruitment and
RR, 0.96; 95% CI, 0.671.37; low Future research opportunities. The alterations in chest wall mechanics (38).
condence) or ventilator-free days (VFDs) balance of potential benets and harms of Early trials demonstrated increased
(two studies, 977 patients; 0.03 more VFDs; spontaneous breathing in patients with oxygenation (39, 40), but this did not
95% CI, 25.88 to 5.95; low condence) ARDS is unknown. It has been suggested translate into reduced mortality.
between groups. Meta-regression showed a that benets might include improved However, post hoc analyses of subgroups
signicant inverse association between oxygenation, more homogenous aeration, with more severe lung injury (e.g., more
larger tidal volume gradient (i.e., difference reduced sedative requirements, and lower severe hypoxemia) suggested benet to
in tidal volume between LTV and control risk for ventilator-induced diaphragmatic prone positioning (41).
groups) and the relative risk of mortality dysfunction (32). However, it may not Summary of the evidence. Prone
associated with LTV (P = 0.002); trials with always be possible to achieve strict positioning has been evaluated in eight
larger tidal volume gradients showed lower control of tidal volumes and inspiratory RCTs, including 2,129 patients (39, 40,
mortality risk with LTV. Sensitivity analysis pressures in spontaneously breathing 4247). There was no signicant difference
that also included trials of a protocolized patients with ARDS. Moreover, some in mortality for patients in the prone versus
LTV/high PEEP cointervention showed studies have suggested that abrogating supine groups (eight studies, 2,129 patients;
signicantly reduced mortality with LTV early spontaneous breathing in patients RR, 0.84; 95% CI, 0.681.04; moderate
(nine studies, 1,629 patients; RR, 0.80; 95% with severe ARDS may limit the risk for condence). However, in prespecied
CI, 0.660.98). Compared with trials VILI and decrease mortality (3335). subgroup analyses (based on proning
without a high PEEP cointervention, This issue is a common and challenging duration, ARDS severity, concomitant LTV
LTV/high PEEP was associated with a problem in the management of ARDS. ventilation), prone positioning reduced
greater mortality benet (RR, 0.58; 95% CI, To resolve this, RCTs of spontaneous mortality in trials with prone duration
0.410.82; P = 0.05 for interaction). breathing under partially assisted greater than 12 h/d (ve studies, 1,002
Recommendation. We recommend that ventilation versus strictly controlled patients; RR, 0.74; 95% CI, 0.560.99; high
adult patients with ARDS receive mechanical ventilation in patients with condence) and patients with moderate or
mechanical ventilation with strategies that ARDS are needed. In addition, RCTs are severe ARDS (ve studies, 1,006 patients;
limit tidal volumes (48 ml/kg PBW) and needed to determine whether further RR, 0.74; 95% CI, 0.540.99; moderate

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condence) (P = 0.05 for interaction in both positioning in patients with moderate CI, 0.711.24; low condence). However,
analyses) (40, 4447). Moreover, the ARDS (with a Pa O2 /FI O 2 of 101150), for our recommendation, we strongly
committee considered a patient-level based on the inclusion criteria for the considered evidence from the RCT that
metaanalysis of four earlier RCTs PROSEVA trial (47), due to lower used LTV with higher PEEP in the
demonstrating lower mortality in condence in the balance between control group that reported signicantly
patients with severe ARDS at baseline desirable as compared with undesirable higher mortality with HFOV (RR, 1.41;
(14), with subsequent conrmation of outcomes in this subgroup of patients. 95% CI, 1.121.79) (57) as well as a large
this nding in the PROSEVA (Proning Future research opportunities. The pragmatic RCT that showed no benet
Severe ARDS Patients) trial (mean 6 most recent RCT demonstrating a with HFOV (adjusted odds ratio, 1.03;
baseline PaO2 /FI O 2, 100 6 30 in the prone dramatic mortality benet in patients 95% CI, 0.751.40) (56). There was no
group) (47). Prone positioning was with ARDS was conducted in expert signicant difference in oxygenation at
signicantly associated with higher rates centers with clinicians skilled in the use of 24 hours (ve studies, 1,583 patients;
of endotracheal tube obstruction (three prone ventilation (47). As a result, it is 10 mm Hg higher; 95% CI, 216 to 27 mm
studies, 1,594 patients; RR, 1.76; 95% CI, important to develop implementation Hg; moderate condence), carbon
1.242.50; moderate condence) and strategies to translate the ndings of the dioxide tension at 24 hours (ve studies;
pressure sores (three studies, 1,109 PROSEVA trial into practice in all 1,591 patients; 1 mm Hg higher; 95% CI,
patients; RR, 1.22; 95% CI, 1.061.41; centers caring for patients with severe 23 to 5 mm Hg; moderate condence),
high condence). There was no ARDS. It is unknown whether higher or barotrauma (two studies, 673 patients;
signicant difference in barotrauma PEEP can potentiate the lung-protective RR, 1.15; 95% CI, 0.612.17; moderate
between groups (four studies, 988 effects of prone positioning. Trials of condence).
patients; RR, 0.77; 95% CI, 0.481.24; prone positioning to date have used Recommendation. We recommend that
moderate condence). moderate levels of PEEP (48). Further HFOV not be used routinely in patients with
Recommendation. We recommend that research is required to evaluate the benet moderate or severe ARDS (strong
adult patients with severe ARDS receive of higher PEEP during prone positioning. recommendation, moderate-high
prone positioning for more than 12 hours condence in effect estimates).
per day (strong recommendation, Question 3: Should Patients with Justication and implementation
moderate-high condence in effect ARDS Receive High-Frequency considerations. This recommendation is
estimates). Oscillatory Ventilation? based primarily on the results of the two
Justication and implementation recent large, multicenter RCTsone that
considerations. This strong Background. High-frequency oscillatory reported signicant harm associated with
recommendation comes from moderate- ventilation (HFOV) uses novel HFOV (57) and the other no benet (56).
high condence in the moderate mechanisms of alveolar ventilation, In conjunction with the ndings from
magnitude of effects on highly valued permitting the delivery of very small tidal our study-level metaanalysis, this strong
outcomes (i.e., mortality) from our volumes at higher mean airway pressures recommendation comes from moderate-
prespecied subgroup analyses, as well as (49). By simultaneously recruiting high condence in the magnitude of
a preexisting patient-level metaanalysis, collapsed lung units and minimizing tidal effects on highly valued outcomes (e.g.,
and the moderate-high condence that stress and strain, HFOV offers a mortality) and the moderate-high
undesirable outcomes are modest theoretically attractive mode of lung condence that undesirable outcomes are
(i.e., endotracheal tube obstruction and protection (50, 51). HFOV requires signicant and their avoidance is highly
pressure sores). Although avoidance of specialized expertise, and patients must valued.
these undesirable outcomes is valued, the be heavily sedated to prevent tidal Future research opportunities. Given
balance of desirable compared with inspiratory efforts. The overall impact of the lack of benet and the potential for
undesirable benets favors the HFOV on patient outcomes in ARDS was harm demonstrated in the most recent
intervention. However, not all committee controversial (13). RCTs of HFOV in ARDS, future research
members agreed with the strong (rather Summary of the evidence. HFOV was on this technique will require a
than conditional) recommendation for evaluated in six RCTs including 1,715 substantial shift in how HFOV is used.
the use of prone position in patients with patients (5257). Our primary analysis Protocols using lower mean airway
severe ARDS. Two dissenting members excluded trials that used cointerventions pressure to avoid overdistention and
pointed out that the recommendation (e.g., higher PEEP) or did not mandate hemodynamic compromise, perhaps
was made based on the subgroup analysis LTV in the control group (52, 54, 55). For titrated to individual patient respiratory
heavily weighted by a single clinical trial our primary analysis, there was no mechanics (e.g., guided by
and the potential risks that include not signicant difference in mortality for transpulmonary pressure) (58), or
only endotracheal tube obstruction and patients in the HFOV versus control targeting different frequencies (45), may
pressure ulcers but also those related to group (three studies, 1,371 patients; RR, lead to different results. Finally, the role
increased sedation and limited 1.14; 95% CI, 0.881.48; high condence) of HFOV as rescue therapy in patients
mobilization in the prone position. (53, 56, 57). When considering all six with severe ARDS with refractory
Finally, there was a lack of consensus RCTs, there also was no signicant hypoxemia remains to be determined.
from the panel on providing a difference in mortality between groups A forthcoming individual patient data
conditional recommendation for prone (six studies, 1,705 patients; RR, 0.94; 95% metaanalysis (IPDMA) of the recent

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RCTs of HFOV (56, 57) may provide IPDMA of higher versus lower PEEP trials, increased lung weight from interstitial and
additional data on this indication. supporting a statistically signicant alveolar edema (70). Atelectasis exacerbates
reduction in mortality in patients with lung injury during mechanical ventilation
Question 4: Should Patients with moderate or severe ARDS (65). Because the by reducing the size of the lung available for
ARDS Receive Higher, as Compared IPDMA combined multiple different tidal ventilation (22) and by amplifying
with Lower, PEEP? strategies, the recommendation for higher stress at the interface between atelectatic
PEEP in moderate or severe ARDS is and aerated lung and in alveolar units
Background. Although higher PEEP may difcult to operationalize. A reasonable subjected to cyclic tidal recruitment and
improve alveolar recruitment, reduce lung starting point would be to implement a derecruitment (23). Both higher PEEP and
stress and strain, and prevent atelectrauma higher PEEP strategy that was used in lung RMs (7072) can reduce atelectasis
in some patients with ARDS, potential risks large RCTs included in the IPDMA and increase end-expiratory lung volume.
include injury from end-inspiratory alveolar (i.e., ALVEOLI [Assessment of Low Tidal RMs involve transient elevations in applied
overdistention, increased intrapulmonary Volume and Elevated End-Expiratory airway pressures intended to open
shunt, increased dead space, and higher Volume to Obviate Lung Injury] [59], LOV (recruit) collapsed lung and increase the
pulmonary vascular resistance leading to cor [Lung Open Ventilation] Study [60], number of alveolar units participating in
pulmonale. ExPRESS [Expiratory Pressure] [61]). tidal ventilation (73). A variety of
Summary of the evidence. Higher Importantly, changes in PEEP will inuence maneuvers have been described, including
versus lower PEEP strategies were evaluated inspiratory plateau pressure, and clinicians prolonged high continuous positive airway
in eight RCTs, including 2,728 patients (21, should consider the risks and benets for the pressure (3040 cm H2O), progressive
22, 5964). Mean 6 SD PEEP was 15.1 6 individual patient of increasing PEEP when incremental increases in PEEP at constant
3.6 versus 9.1 6 2.7 cm H2O in the higher plateau pressure is greater than or equal to driving pressure (63), and high driving
and lower PEEP groups on Day 1, 30 cm H2O. In conjunction with the ndings pressures (74). RMs are usually associated
respectively. Our primary analysis excluded from our study-level metaanalysis, this with short-term physiological benets,
two trials that did not use LTV in the lower conditional recommendation comes from including reduced intrapulmonary
PEEP control groups (21, 22). There was no moderate condence in the small magnitude shunt and increased pulmonary
signicant difference in mortality for of effects on highly valued outcomes (e.g., compliance (72, 73), but may be
patients receiving higher versus lower PEEP mortality) and moderate condence that any associated with complications, including
(six studies, 2,580 patients; RR, 0.91; 95% effects on undesirable outcomes are small hemodynamic compromise and
CI, 0.801.03; moderate condence) and that avoidance of these undesirable barotrauma (74).
(5964). Higher PEEP strategies were not outcomes is not highly valued. Summary of the evidence. RMs were
associated with signicant differences in Future research opportunities. The best evaluated in six RCTs, including 1,423
barotrauma, new organ failure, or VFDs as method to set PEEP in patients with ARDS patients (21, 60, 63, 64, 75, 76). The type of
compared with a lower PEEP strategy remains uncertain. Given the lack of RM varied widely among trials, and our
(moderate condence). Oxygenation consistent efcacy when PEEP is adjusted primary analysis excluded ve trials that
(PaO2/FIO2 ratio) was signicantly higher in according to oxygenation (59, 60), other used higher PEEP as a cointervention with
patients randomized to higher PEEP methods based on lung mechanics or RMs (21, 60, 63, 64, 75). In the only trial
(61 mm Hg higher; 95% CI, 4677 mm imaging have been proposed and require without cointervention, RMs were
Hg). However, for our recommendation, we evaluation in future studies (67). signicantly associated with lower mortality
also considered evidence from an IPDMA Individualizing PEEP titration by targeting (one study, 110 patients; RR, 0.62; 95% CI,
of three large RCTs of higher versus lower the transpulmonary plateau pressure is an 0.390.98; low condence) (76). When
PEEP (65). In this study, patients with alternative strategy. A pilot RCT using considering all six RCTs, RMs were
moderate or severe ARDS (PaO2/FIO2 < 200) transpulmonary pressureguided PEEP signicantly associated with lower mortality
randomized to higher PEEP had selection yielded promising results (62), (six studies, 1,423 patients; RR, 0.81; 95%
signicantly lower mortality (adjusted RR, and a larger-scale multicenter RCT is CI, 0.690.95; moderate condence). There
0.90; 95% CI, 0.811.00), with no currently underway (EPVent2, ClinicalTrials. was no evidence of heterogeneity (P = 0.21)
signicant effect among patients with mild gov NCT01681225). Developing and despite a higher PEEP cointervention used
ARDS (adjusted RR, 1.29; 95% CI, validating simple tools to assess lung in ve of six trials. RMs were also associated
0.911.83; P = 0.02 for comparison with recruitability, such as the oxygenation with higher oxygenation (PaO2/FIO2 ratio) at
moderate/severe ARDS subgroup). response to PEEP (68, 69), may help to 24 hours (six studies, 1,400 patients; 52 mm
Recommendation. We suggest that adult identify patients with ARDS who are most Hg higher; 95% CI, 2381; low condence)
patients with moderate or severe ARDS receive likely to benet from higher PEEP and could and reduced the need for rescue therapy
higher rather than lower levels of PEEP be used to enrich the study population of (two studies, 1,003 patients; RR, 0.64; 95%
(conditional recommendation, moderate future RCTs of higher PEEP strategies (32). CI, 0.350.93; moderate condence). RMs
condence in effect estimates). were not signicantly associated with
Justication and implementation Question 5: Should Patients with barotrauma (four studies, 1,293 patients;
considerations. Given the important ARDS Receive RMs? RR, 0.84; 95% CI, 0.461.55; low
advantages of an IPDMA over conventional condence) and rates of hemodynamic
metaanalysis (66), this recommendation is Background. Patients with ARDS have compromise (three studies, 330 patients;
based primarily on the results of the dependent atelectasis due in part to RR, 1.30; 95% CI, 0.921.83).

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AMERICAN THORACIC SOCIETY DOCUMENTS

Recommendation. We suggest that have advised caution about its role in the NCT01470703). Other types of
adult patients with ARDS receive RMs management of severe ARDS (79, 84). extracorporeal support, such as
(conditional recommendation, Summary of the evidence. In a single extracorporeal CO2 removal (ECCO2R),
lowmoderate condence in the effect RCT including 180 patients, patients with may have a role in facilitating ultra-
estimates). ARDS were randomized to stay at their protective mechanical ventilation in
Justication and implementation hospitals without ECMO or be transferred patients with ARDS by allowing further
considerations. Although rates of to a single tertiary hospital with ECMO reductions in tidal volume and airway
hemodynamic compromise differed capability (85). This trial found no pressure (87, 88). A multicenter pilot study
considerably between trials reporting signicant difference in mortality for examining the feasibility of using ECCO2R
such events (typically reported as patients transferred for VV ECMO versus to allow a reduction in tidal volume to
transient hypotension), clinicians should not transferred and provided conventional 4 ml/kg PBW in patients with
be cautious about RMs in patients with mechanical ventilation (RR, 0.75; 95% CI, moderate/severe ARDS is currently
preexisting hypovolemia or shock. This 0.531.06; low condence). A secondary underway (SUPERNOVA [Strategy of
conditional recommendation comes from metaanalysis incorporating observational UltraProtective Lung Ventilation with
low-moderate condence in the small- studies also found no signicant difference Extracorporeal CO2 Removal for New-
moderate magnitude of effects on highly in mortality (eight studies, 1,151 patients; Onset Moderate to Severe ARDS],
valued outcomes (e.g., mortality), RR, 0.96; 95% CI, 0.671.39; very low ClinicalTrials.gov NCT02282657) and will
indirectness in the majority of included condence). There was no signicant inform the design of a larger, multicenter
studies (which were strongly confounded difference in life-threatening bleeding efcacy RCT. In addition, a multicenter
by cointerventions), and the low- between groups (three studies, 371 patients; study examining the use of ECCO2R with a
moderate condence that undesirable RR, 2.77; 95% CI, 0.4417.34; very low target tidal volume of 3 ml/kg PBW in
outcomes are modest and their avoidance condence). patients with moderately severe hypoxic
is not highly valued. Recommendation. Additional evidence respiratory failure will commence
Future research opportunities. The is necessary to make a denitive shortly (REST [Protective Ventilation with
optimal method, timing, and target recommendation for or against the use Veno-venous Lung Assist in Respiratory
population for RMs, as well as the role for of ECMO in patients with severe ARDS. In the Failure], ClinicalTrials.gov NCT02654327).
concomitant changes in PEEP, remain interim, we recommend ongoing research
uncertain and require further study. Two measuring clinical outcomes among patients
ongoing RCTs may provide additional with severe ARDS who undergo ECMO. Conclusions
insights into the efcacy of RMs in the Justication and implementation
routine management of patients with ARDS considerations. There is insufcient Signicant advances have been made in the
and may impact our condence in the evidence to make a recommendation ventilatory management of ARDS in the last
estimates of effect (ART [Alveolar regarding the use of ECMO in patients few decades. It is expected that future
Recruitment for Acute Respiratory Distress with ARDS. The only recent RCT iterations of the guideline will address
Syndrome Trial], ClinicalTrials.gov considered (85) had limitations including: questions related to pharmacologic
NCT01374022; and PHARLAP [Permissive (1) the use of a composite primary therapies to facilitate mechanical ventilation
Hypercapnia, Alveolar Recruitment and endpoint (i.e., disability-free survival at (e.g., neuromuscular blockade), adjunctive
Low Airway Pressure], ClinicalTrials.gov 6 mo), (2) incomplete application of the measures (e.g., inhaled vasodilators), and
NCT01667146). intervention (24% of patients randomized other ventilatory modes (e.g., airway
to the intervention group did not receive pressure release ventilation). Clinicians
Question 6: Should Patients with ECMO), (3) the lack of standardized LTV in managing patients with ARDS should
ARDS Receive Extracorporeal the control group, and (4) cointervention personalize decisions for their patients,
Membrane Oxygenation? with transfer to a high-volume referral center. particularly regarding the conditional
In the interim, we recommend evidence- recommendations in this guideline, and
Background. Venovenous extracorporeal based use of lung-protective ventilation and they should be careful when comparing
membrane oxygenation (VV ECMO) is a early medical management for patients with the relative benets of one intervention
system that drains blood from a large central severe ARDS before use of ECMO. over another if they have the same rating.
vein and pumps it through a gas-exchange Future research opportunities. Further The potential benets or synergies of
device that oxygenates the blood and research is needed to clarify the potential combined or sequential treatments with
removes carbon dioxide. The blood is then efcacy of ECMO for patients with interventions included in this guideline have
reinfused back into a large central vein (77). severe ARDS as well as the role of not been explicitly studied, and therefore no
Although initial results were disappointing extracorporeal support in patients with recommendations have been made. Most
(78, 79), extracorporeal support techniques mild/moderate ARDS (86). More data recent studies of ventilatory interventions,
have been improved and applied extensively will be coming from an international, however, have used LTV ventilation in
in recent years after more encouraging multicenter RCT comparing VV ECMO recognition of supportive clinical and
reports during the 2009 H1N1 pandemic to conventional mechanical ventilation experimental evidence (70). Novel
(8082). Despite the growing use of VV (EOLIA [Extracorporeal Membrane analytical strategies (e.g., network
ECMO in patients with ARDS (83), there is Oxygenation for Severe Acute Respiratory metaanalysis) and future RCTs may
limited evidence supporting its use, and some Distress Syndrome]; ClinicalTrials.gov provide additional insights to important

American Thoracic Society Documents 1259


AMERICAN THORACIC SOCIETY DOCUMENTS

questions of bundled or sequential clinical trials of patients receiving Finally, these guidelines should be updated
interventions. Efforts to improve the mechanical ventilation may also improve as pertinent new evidence becomes
standardization of outcomes reported in the ability to compare trial results (89). available. n

This Clinical Practice Guideline was prepared by the ATS/ESICM/SCCM Ad Hoc Committee on Mechanical Ventilation in Adult Patients
with ARDS.

Members of the committee are as OGNJEN GAJIC, M.D., M.SC. Intensive Care Society. A.S.S. served as a
follows: consultant for Baxter Healthcare, Gambro,
DEAN HESS, R.R.T., PH.D. Maquet Cardiopulmonary, and Novalung/
LAURENT J. BROCHARD, M.D. (Co-Chair) EILEEN RUBIN, J.D.3 Xenios; and served as a speaker for Draeger
EDDY FAN, M.D., PH.D. (Co-Chair) MAUREEN SECKEL, A.P.R.N., M.S.N., D.E. Medical. L.G. served on an advisory committee
for Grifols; and served as a speaker for Baxter,
Conventional Mechanical Ventilation Author Disclosures: L.J.B. received research B. Braun, GE Healthcare, Grifols, Kedrion,
Subcommittee: support from Air Liquide, Draeger, Fisher & and KCI. D.F.M. served as a consultant for
ROY G. BROWER, M.D. (Chair) Paykel Healthcare, General Electric, Maquet GlaxoSmithKline, Bayer, Boehringer Ingelheim,
Critical Care, Medtronic Covidien, Philips Peptinnovate, and SOBI; has intellectual
DANIEL TALMOR, M.D., M.P.H. Respironics, and Vygon. E.F. served as a property that has not been commercialized with
B. TAYLOR THOMPSON, M.D. speaker for St. Jude Medical. R.G.B. served as The Queens University of Belfast; and received
ALLAN J. WALKEY, M.D., M.SC.1 a consultant for Questcor. D.T. served as a research support and served on an advisory
consultant and a speaker for Hamilton Medical. committee for GlaxoSmithKline. R.B. served on
Lung Recruitment Strategies Subcommittee: B.T.T. served as a consultant for Abbott, an advisory committee, received research
GORDON D. RUBENFELD, M.D., M.SC. (Chair) Alexion Pharmaceuticals, Asehi Kasei, Bayer support, has stocks, stock options, or other
MARCELO B. P. AMATO, M.D., PH.D. HealthCare Pharmaceuticals, BioAegis, equity interests and has intellectual property that
DaVita, Hemodec, Ra Pharmaceuticals, will be commercialized for Ventec Life Systems;
NIALL D. FERGUSON, M.D., M.SC. Sirius Genomics, US Biotest, and Vertex and served on an advisory committee, as a
EWAN C. GOLIGHER, M.D.1 Pharmaceuticals; served on a data safety and consultant, and received research support from
monitoring board for Faron Pharmaceuticals, Mallinckrodt. O.G. had stock or options with
Adjunctive Interventions Subcommittee: Ferring Labs, and Roche Genentec; is an author and commercialized intellectual property
V. MARCO RANIERI, M.D., PH.D. (Chair) for UpToDate; received research support from sold to Ambient Clinical Analytics. D.H.
JORDI MANCEBO, M.D. Eli Lilly; served on an advisory committee for served as a consultant for Bayer HealthCare
Abbott, Aerogen, Boehringer Ingelheim, Ferring
LAVEENA MUNSHI, M.D.1 Labs, GlaxoSmithKline, InterMune, Regeneron
Pharmaceuticals, Philips Respironics, and
Ventec; is an author for and receives royalties
ANTONIO PESENTI, M.D. Pharmaceuticals, and Sanofi Aventis; and from Jones and Bartlett, McGraw Hill, and
served as a speaker for DaVita. A.J.W. was a UpToDate; received an honorarium for writing a
Methodology Subcommittee: writer for and received royalties from UpToDate. CME activity for Postgraduate Healthcare
MAUREEN O. MEADE, M.D., M.SC. (Chair) G.D.R. served on an advisory committee for Education; served as a consultant for Breathe
NEILL K. J. ADHIKARI, M.D., M.SC. Ikaria. M.B.P.A. received research support Technologies, Merck, Pari, and ResMed; was a
from Timpel and served as a consultant for speaker for Maquet; served as a consultant and
JAN BROZEK, M.D., PH.D.2 Medtronic. V.M.R. served on the advisory speaker for Medtronic USA; and served as
CAROL L. HODGSON, PH.D. committee for Hemodec and ALung; and the editor in chief of Respiratory Care for
ELIZABETH ULERYK, M.L.S. received research support from Faron Daedalus Enterprises. N.D.F., E.C.G., L.M.,
Pharmaceuticals and Maquet. J.M. received M.O.M., N.K.J.A., J.B., E.U., H.W., L.D.S., E.R.,
HANNAH WUNSCH, M.D., M.SC. research support and served as a speaker for and M.S. report no relationships with relevant
Experimental Evidence Subcommittee: Covidien; served on an advisory committee for commercial interests.
Faron Pharmaceuticals; received research
ARTHUR S. SLUTSKY, M.D. (Chair) support from Maquet Critical Care; served on a
LORENZO DEL SORBO, M.D.1 data safety and monitoring board for Air Liquide; Acknowledgment: The authors thank patients
LUCIANO GATTINONI, M.D. served on an advisory committee for Air Liquide participating in clinical studies and investigators and
DANIEL F. MCAULEY, M.D. and ALung; and served as a consultant for Air sponsors of published reports of clinical studies; the
Liquide and Braun. A.P. served as a consultant American Thoracic Society (ATS), European Society
Interprofessional Subcommittee: for NovaLung and Maquet Cardiopulmonary; of Intensive Care Medicine, and Society of Critical
served on an advisory committee for Baxter Care Medicine; Kevin Wilson, M.D., editor, ATS
RICHARD BRANSON, R.R.T., M.SC. Healthcare and Xenios; and has intellectual documents; peers and external reviewers for
1 property that has not been commercialized for providing useful input; Judy Corn, John Harmon, and
Junior members
2
extracorporeal CO2 removal devices. C.L.H. the ATS Documents and Implementation Committee,
ATS methodologist served as the co-chair of the PHARLAP RCT ATS; and Venika Manoharan, Sunnybrook Health
3
President of the ARDS Foundation clinical trial for the Australian and New Zealand Sciences Centre, Toronto, Ontario, Canada.

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