Papazian et al. Ann. Intensive Care (2019) 9:69 https://doi.org/10.1186/s13613-019-0540-9
￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼ ￼
Laurent Papazian1*, Cécile Aubron2, Laurent Brochard3, Jean‐Daniel Chiche4, Alain Combes5, Didier Dreyfuss6, Jean‐Marie Forel1, Claude Guérin7, Samir Jaber8, Armand Mekontso‐Dessap9, Alain Mercat10, Jean‐Christophe Richard11, Damien Roux6, Antoine Vieillard‐Baron12 and Henri Faure13
Fifteen recommendations and a therapeutic algorithm regarding the management of acute respiratory distress syndrome (ARDS) at the early phase in adults are proposed. The Grade of Recommendation Assessment, Develop‐ ment and Evaluation (GRADE) methodology has been followed. Four recommendations (low tidal volume, plateau pressure limitation, no oscillatory ventilation, and prone position) had a high level of proof (GRADE 1 + or 1 −); four (high positive end‐expiratory pressure [PEEP] in moderate and severe ARDS, muscle relaxants, recruitment maneu‐ vers, and venovenous extracorporeal membrane oxygenation [ECMO]) a low level of proof (GRADE 2 + or 2 −); seven (surveillance, tidal volume for non ARDS mechanically ventilated patients, tidal volume limitation in the presence of low plateau pressure, PEEP > 5 cmH2O, high PEEP in the absence of deleterious e ect, pressure mode allowing spon‐ taneous ventilation after the acute phase, and nitric oxide) corresponded to a level of proof that did not allow use of the GRADE classi cation and were expert opinions. Lastly, for three aspects of ARDS management (driving pressure, early spontaneous ventilation, and extracorporeal carbon dioxide removal), the experts concluded that no sound recommendation was possible given current knowledge. The recommendations and the therapeutic algorithm were approved by the experts with strong agreement.
Acute respiratory distress syndrome (ARDS) is an in am- matory process in the lungs that induces non-hydrostatic protein-rich pulmonary oedema. e immediate conse- quences are profound hypoxemia, decreased lung com- pliance, and increased intrapulmonary shunt and dead space. e clinicopathological aspects include severe in ammatory injury to the alveolar-capillary barrier, sur- factant depletion, and loss of aerated lung tissue.
e most recent de nition of ARDS, the Berlin de – nition, was proposed by a working group under the aegis of the European Society of Intensive Care Medi- cine . It de nes ARDS by the presence within 7 days of a known clinical insult or new or worsening respira- tory symptoms of a combination of acute hypoxemia
1 Service de Médecine Intensive ‐ Réanimation, Hôpital Nord, Chemin des Bourrely, 13015 Marseille, France
Full list of author information is available at the end of the article
(PaO2/FiO2≤300 mmHg), in a ventilated patient with a positive end-expiratory pressure (PEEP) of at least 5 cmH2O, and bilateral opacities not fully explained by heart failure or volume overload. e Berlin de – nition uses the PaO2/FiO2 ratio to distinguish mild ARDS (200<PaO2/FiO2≤300 mmHg), moderate ARDS (100 < PaO2/FiO2 ≤ 200 mmHg), and severe ARDS (PaO2/ FiO2 ≤ 100 mmHg).
Much information on the epidemiology of ARDS has accrued from LUNG SAFE, an international, multicenter, prospective study conducted in over 29,000 patients in 50 countries . During this study, ARDS accounted for 10% of admissions to intensive care unit (ICU) and 23% of ventilated patients. Hospital mortality, which increased with the severity of ARDS , was about 40%, and reached 45% in patients presenting with severe ARDS [2–4]. Signi cant physical, psychological, and cognitive sequelae, with a marked impact on quality of life, have been reported up to 5 years after ARDS .
© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
￼ ￼ ￼ ￼ ￼ ￼ ￼
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 2 of 18
One of the most important results of the LUNG SAFE study was that ARDS was not identi ed as such by the primary care clinician in almost 40% of cases . is was particularly so for mild ARDS, in which only 51% of cases were identi ed . When all ARDS criteria were met, only 34% of ARDS patients were identi ed, suggest- ing that there was a delay in adapting the treatment, in particular mechanical ventilation . is is the main reason why these formal guidelines are not limited to patients presenting with severe ARDS, but are intended for application to all mechanically ventilated intensive care patients.
Results from the LUNG SAFE study suggest that the ventilator settings used did not fully respect the princi- ples of protective mechanical ventilation . Plateau pres- sure was measured in only 40% of ARDS patients . And only two-thirds of patients for whom plateau pressure was reported were receiving protective mechanical ventilation (tidal volume≤8 mL/kg predicted body weight [PBW] and plateau pressure≤30 cmH2O) . Analysis of the LUNG SAFE results also shows a lack of relation between PEEP and the PaO2/FIO2 ratio . In contrast, there was an inverse relation between FIO2 and SpO2, suggesting that the clinicians used FIO2 to treat hypoxemia. Lastly, prone positioning was used in just 8% of patients present- ing with ARDS, essentially as salvage treatment .
e reduction in mortality associated with ARDS over the last 20 years seems to be explained largely by a decrease in ventilator-induced lung injury (VILI). VILI is essentially related to volutrauma closely associated with “strain” and “stress”. Lung stress corresponds to transpul- monary pressure (alveolar pressure–pleural pressure), and lung strain refers to the change in lung volume indexed to functional residual capacity of the ARDS lung at zero PEEP. So, volutrauma corresponds to generalized excess stress and strain on the injured lung [6–8]. High-quality CT scan studies and physiological studies have revealed that lung lesions are unequally distributed, the injury or atelectasis coexisting with aerated alveoli of close-to-nor- mal structure . ARDS is not a disease; it is a syndrome de ned by a numerous clinical and physiological criteria. It is therefore not surprising that lung-protective ventila- tory strategies that are based on underlying physiological principles have been shown to be e ective in improving outcome. Minimizing VILI thus generally aims reducing volutrauma (reduction in global stress and strain). Low- ering airway pressures has the theoretical dual bene t of minimizing overdistension of the aerated areas and miti- gating negative hemodynamic consequences.
e current SRLF guidelines are more than 20 years old and so there was a pressing need to update them. e main aim with these formal guidelines was voluntar- ily to limit the topics to the best studied elds, so as to
provide practitioners with solid guidelines with a high level of agreement between experts. Certain very impor- tant aspects of ARDS management were deliberately not addressed because there is insu cient assessment of their e ects on prognosis (respiratory rate, mechanical power, target oxygenation, pH, PaCO2…). We also limited these guidelines to adult patients, to early phase of ARDS ( rst few days), and to invasive mechanical ventilation.
ese guidelines have been formulated by an expert work- ing group selected by the SRLF. e organizing commit- tee rst de ned the questions to be addressed and then designated the experts in charge of each question. e questions were formulated according to a Patient Inter- vention Comparison Outcome (PICO) format after a rst meeting of the expert group. e literature was analyzed using Grade of Recommendation Assessment, Develop- ment and Evaluation (GRADE) methodology. A level of proof was de ned for each bibliographic reference cited as a function of the type of study and its methodological quality. An overall level of proof was determined for each endpoint. e experts then formulated guidelines accord- ing to the GRADE methodology (Table 1).
A high overall level of proof enabled formulation of a “strong” recommendation (should be done… GRADE 1+, should not be done… GRADE 1−). A moderate, low, or very low overall level of proof led to the drawing up of an “optional” recommendation (should probably be done… GRADE 2+, should probably not be done… GRADE 2−). When the literature was inexistent or insu cient, the question could be the subject of a recom- mendation in the form of an expert opinion (the experts suggest…). e proposed recommendations were pre- sented and discussed at a second meeting of the expert group. Each expert then reviewed and rated each recom- mendation using a scale of 1 (complete disagreement) to 9 (complete agreement). e collective rating was done using a GRADE grid methodology. To approve a rec- ommendation regarding a criterion, at least 50% of the experts had to agree and less than 20% had to disagree. For a strong agreement, at least 70% of the experts had to agree. In the absence of strong agreement, the recom- mendations were reformulated and rated again, with a view to reaching a consensus (Table 2).
Area 1: Evaluation of ARDS management
R1.1 – e experts suggest that the e cacy and safety of all ventilation parameters and thera- peutics associated with ARDS management should be evaluated at least every 24 h.
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 3 of 18
Table 1 Recommendations according to the GRADE methodology
High level of proof Moderate level of proof Insu cient level of proof Moderate level of proof High level of proof Insu cient level of proof
Evaluation of the e cacy and safety of mechanical ven- tilation settings and treatments is a cornerstone of the early phase of the management of ARDS patients. As shown in these formal guidelines, the settings of venti- lation parameters, such as PEEP, are based on their e – cacy and tolerance. Moreover, the indication for some treatments depends on the severity of ARDS and these treatments will only be implemented when there is insuf- cient response to rst-line treatments.
Grade 1 + Grade 2 + Expert opinion Grade 2 − Grade 1 −
Figure 1 shows the treatments implemented to patients with ARDS based on the severity of respiratory distress. e decision to initiate some treatments is taken after a “stabilization” phase  that includes optimization of mechanical ventilation as the rst step of management. Early evaluation of e cacy based on the PaO2/FiO2 ratio is necessary in order to discuss the relevance of neu- romuscular blocking agents and of prone positioning (Fig. 1).
e safety of drug therapies and procedures must also be regularly evaluated. ese guidelines also address the
Fig. 1 Therapeutic algorithm regarding early ARDS management (EXPERT OPINION)
Recommendations according to the GRADE methodology
Strong recommendation “…should be done…”
“… should probably be done…”
Recommendation in the form of an expert opinion “The experts suggest…”
“… should probably not be done…”
Strong recommendation “…should not be done…”
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 4 of 18
main safety problems of the treatments. Literature sup- port for such practices is lacking, and they are guided by good clinical sense.
Indeed, data are scarce on the bene ts of regular assessment of ventilation settings and/or disease sever- ity in ARDS patients. A single-center observational study has shown the value of systematic evaluation of respira- tory mechanics during ARDS in the initial phase (mostly in the rst 48 h) . In this study, evaluation of the passive mechanics of the lung and thoracic cage, of the response to PEEP, and of alveolar recruitment prompted changes in ventilation parameters in most patients (41 of 61 analyzed). ese changes were associated with improvements in plateau pressure (−2 cmH2O on aver- age), driving pressure (−3 cmH2O on average), and oxy- genation index .
It is di cult to de ne how often to assess ventilation parameters and treatments in ARDS. It seems that a fre- quency at least similar to that proposed for the evalua- tion of criteria for weaning from the ventilator (i.e. daily) is reasonable . Nonetheless, more frequent assess- ment might be necessary and bene t in some cases.
Area 2: Tidal volume management
Tidal volume adjustment
R2.1.1 – A tidal volume around 6 mL/kg of pre- dicted body weight (PBW) should be used as a rst approach in patients with recognized ARDS, in the absence of severe metabolic acido- sis, including those with mild ARDS, to reduce
mortality. GRADE 1 +, STRONG AGREEMENT
R2.1.2 – e experts suggest a similar approach for all patients on invasive mechanical ventila- tion and under sedation in ICU, given the high rate of failure to recognize ARDS and the impor- tance of rapidly implementing pulmonary pro- tection.
To control potentially deleterious increases in PaCO2 (which raise pulmonary arterial pressure), a relatively high respiratory rate of between 25 and 30 cycles/min should be adopted rst. Too high a rate, however, engen- ders a risk of dynamic hyperin ation and also increases each minute cumulative exposure to potentially risky insu ation. A PaCO2 below 50 mmHg is generally acceptable. A reduction in instrumental dead space is also appropriate, and a heated humidi er should be used in rst intention.
e PBW should be calculated for each patient upon admission as a function of height and sex.
e tidal volume delivered will induce a pressure increase from the PEEP, thus necessitating monitoring of plateau pressure, which should be kept below 30 cmH2O.
Clinicians need to be aware of the potential risks of low tidal volume, such as dyssynchrony and double trig- gering. Guidelines on pressure and volume reduction issued in the late 1980s were based on experimental and clinical data [13–16]. Several randomized clinical trials with rather few subjects in the 1990s found no survival advantage of low tidal volume [17, 18]. A lack of power may, of course, explain these negative results. Note also that these trials were not intended to achieve control of PaCO2, which may have contributed to the deleterious e ects of hypercapnic acidosis in the study arms using reduced tidal volume. Although the clinical evidence is not easy to demonstrate, hypercapnia has unquestion- able side e ects , like increased pulmonary vascu- lar resistance, which can worsen prognosis. In 2000, the ARMA study run by the NHLBI ARDS Network in the USA yielded key data comparing a pulmonary protection strategy using “low” tidal volume, on average 6 mL/kg PBW, a plateau pressure limited to 30 cmH2O, and a res- piratory rate up to 35 breaths/min, with a non-protection strategy using a tidal volume of 12 mL/kg PBW . e use of PBW calculated as a function of sex and height was an important innovation in adapting tidal volume to the expected lung volume. In this study, increased respira- tory rate leading to low-volume ventilation was associ- ated with only a minimal increase in PaCO2, a result that may have contributed to the bene ts of this treatment arm. A 25% reduction in the relative risk of mortality was observed, i.e., a 30–40% decrease in overall mortality. is study had an enormous impact on clinical practice. It was not the rst to use low volumes successfully, that accolade falls to the two-center study by Amato et al., but low tidal volume was combined with higher PEEP, the idea being to reduce driving pressure . Other studies using the same approach as Amato et al. found a similar reduction in mortality . Meta-analyses of tidal vol- ume reduction have often included rather heterogenous studies . e most recent included seven randomized trials in 1481 patients  and concluded that lower mortality was associated with low-volume ventilation in primary analysis (hazard ratio 0.80 [0.66, 0.98]) and found a signi cant relation between tidal volume reduc- tion and the mortality reduction e ect. However, when the studies that combined high PEEP and low volumes were excluded, the e ect of reduced tidal volume was just a non-signi cant trend (0.87 [0.70, 1.08]). Accord- ing to the authors, this suggests, but does not prove, that reduced tidal volumes signi cantly decrease mortality
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 5 of 18
during ARDS. In an observational study, 11,558 ventila- tion parameters were available for 482 ARDS patients identi ed prospectively . e authors compared the patients with volumes of 6.5 mL/kg PBW or less, upon admission, with patients with volumes>6.5 mL/kg PBW (68% of patients), and found that, after adjustment for known confounding factors, an increase of 1 mL/kg PBW in the settings of the initial volume was associated with a 23% increase in risk of death in intensive care (hazard ratio, 1.23; 95% con dence interval, 1.06–1.44; p=0.008) . A secondary increase in tidal volume was also asso- ciated with an increase in mortality risk, but the mortal- ity risk of too high a rst tidal volume was higher than the e ect of the following volumes . In the LUNG SAFE study , tidal volume did not seem to be a sig- ni cant factor in mortality. However, the volume range was limited , which suggests that a “certain degree” of pulmonary protection is used very frequently, but in very few patients with tidal volumes above 10 or below 6 mL/kg. ere was no di erence in survival in the patients whose tidal volume was equal to or greater than the median value of 7.1 mL/kg PBW . In addition, the use of lower tidal volumes in patients with severe ARDS may involve potentially confounding e ects, which are di cult to analyze completely in purely observational data . In all analyses, however, the pressures (peak pressure, plateau pressure, driving pressure, and PEEP) carried more signi cant weight than tidal volume in the prognosis .
R2.2.1 – Once tidal volume is set to around 6 mL/kg PBW, plateau pressure should be moni- tored continuously and should not exceed 30 cmH2O to reduce mortality.
GRADE 1 +, STRONG AGREEMENT
R2.2.2 – e experts suggest that tidal volume should not be increased when the plateau pres- sure is well below 30 cmH2O, except in cases of marked, persistent hypercapnia despite reduc- tion of instrumental dead space and increase of respiratory rate.
Tidal volume, plateau pressure, and driving pressure are closely related (static compliance=tidal volume/plateau pressure-total PEEP) and all participate in VILI. Mechan- ical ventilation should limit VILI, thereby limiting mor- tality. Even if VILI was initially observed on application of a high plateau pressure with a high tidal volume ,
there is less lung injury with the same high plateau pres- sure when the tidal volume is reduced by means of tho- racic sti ness , a situation encountered in the very obese.
e LUNG SAFE study reported that plateau pressure was not monitored in 60% of ventilated ARDS patients and that a non-negligible proportion of patients, although ventilated with a tidal volume below 8 mL/kg PBW, had a plateau pressure above 30 cmH2O, especially those with moderate to severe ARDS . An ancillary study of LUNG SAFE has shown that plateau pressure, which can be modi ed by the intensivist, is strongly and positively correlated with mortality . A high plateau pressure is an independent mortality risk factor, as it re ects either great severity (associated with poor lung compliance) or inadequate mechanical ventilation .
e only way to monitor plateau pressure routinely is to ventilate the patient with an end-inspiratory pause, which should not be too long, so as to facilitate any increase in respiratory rate, or too short, so that the res- pirator can measure the pressure. A pause of 0.2–0.3 s should be used routinely when adjusting the ventilator.
In a given patient, plateau pressure is an imperfect re ection of lung distension . is is particularly so in patients with abnormal compliance of the chest wall, and in some obese patients. e relation between plateau pressure and mortality or the risk of barotrauma is less clear in these patients , which may suggest tolerance of plateau pressure a little above 30 cmH2O, provided that the tidal volume is reduced to limit VILI . In all cases, plateau pressure is no longer associated with baro- trauma when it is kept below 30 cmH2O.
Five controlled and randomized studies compared a strategy of low tidal volume and limited plateau pres- sure with a strategy using higher tidal volume and pla- teau pressure [17, 18, 20, 21, 30]. A signi cant decrease in mortality in the group with limited volume and pressure was observed only in the 2 studies [20, 21] where di er- ence in plateau pressure was particularly large between the 2 strategies tested. When these 5 studies are pooled, there is a strong relation between plateau pressure and mortality . In a recent study in 478 patients, a thresh- old plateau pressure of 29 cmH2O was identi ed beyond which hospital mortality increased . Even in patients ventilated with a driving pressure below 19 cmH2O, a plateau pressure strictly below 30 cmH2O would enable a signi cant reduction in mortality, a greater e ect than that of a driving pressure below 19 cmH2O when the plateau pressure is already below 30 cmH2O . ese results were validated in the same study in a di erent cohort of 300 patients .
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 6 of 18
R2.3 – Available data do not allow a recommen- dation to be made regarding respirator settings based solely on limitation of driving pressure. is limitation can be envisaged as a comple- ment to limitation of plateau pressure in some special instances.
One study retrospectively evaluated the in uence of driv- ing pressure on prognosis by means of a complex statis- tical analysis of nine randomized controlled studies of ventilation strategy (comparison of di erent values of tidal volume and PEEP, during ARDS) . e authors concluded that driving pressure was the best predictor of mortality in these studies. Nonetheless, as the authors themselves acknowledge, this was a retrospective study of studies whose main aim was not to examine the use- fulness of driving pressure. No randomized study has since corroborated the value of limiting driving pres- sure. In contrast, the results of the observational study LUNG SAFE [2, 26] showed no obvious superiority of driving pressure over plateau pressure as a predictor of the risk of mortality. e same was true when the data of two studies showing improved survival during ARDS (by neuromuscular block and by prone positioning) were combined . Prudence regarding the role of driving pressure is advised, and other studies have even yielded some concerns regarding the validity of this physiologi- cal concept. Unlike plateau pressure, which translates dynamic and static lung distension, driving pressure translates dynamic distension. A randomized controlled study of PEEP  (which showed that a “higher PEEP” was associated with higher mortality) seems to call into question the predictive value of driving pressure. Indeed, plateau pressure was lower in the group with lower mor- tality, whereas driving pressure was lower in the group with higher mortality .
Analysis of a series of mechanically ventilated ARDS patients presenting acute cor pulmonale  suggests that when the plateau pressure is kept su ciently low (<27 cmH2O), driving pressure is predictive of cor pul- monale and of mortality. A randomized study designed to demonstrate the predictive value of driving pres- sure should therefore limit plateau pressure to less than 30 cmH2O or even 28 cmH2O in the two groups. Given also that tidal volume should be limited to 6 mL/kg, PEEP is the only ventilator setting that would change. is would therefore amount to comparing two levels of PEEP during ventilation with limited plateau pressure. is is exactly what the EXPRESS study did, and its results were negative .
In practical terms, it would be best rst to measure and limit plateau pressure, an approach which the LUNG SAFE study  has clearly shown is insu ciently used. It is only after limiting plateau pressure su ciently that we can envisage limiting driving pressure in cases when severely altered lung compliance mandates use of insuf- cient PEEP to ensure correct oxygenation (for example, in cases when a PEEP of 6–8 cmH2O and a tidal volume of 6 mL/kg would generate a plateau pressure of about 30 cmH2O in a patient remaining hypoxemic). In this case, it can be useful to reduce driving pressure by fur- ther limiting tidal volume, while increasing PEEP, if this maneuver is well tolerated hemodynamically.
Area 3: Alveolar recruitment
Positive end-expiratory pressure
R3.1.1 – PEEP is an essential component of the management of ARDS and the experts suggest using a value above 5 cmH2O in all patients pre- senting with ARDS. EXPERT OPINION
R3.1.2 – High PEEP should probably be used in patients with moderate or severe ARDS, but not in patients with mild ARDS.
GRADE 2 +, STRONG AGREEMENT
R3.1.3 – e experts suggest reserving high PEEP for patients in whom it improves oxygena- tion without marked deterioration of respira- tory system compliance or hemodynamic status. PEEP settings should be individualized.
PEEP is an integral part of the protective ventilation strategy. e expected bene cial e ect of high PEEP is optimized alveolar recruitment, which, on the one hand, decreases the intrapulmonary shunt, thus improving arterial oxygenation, and, on the other hand, decreases the amount of lung tissue exposed to alveolar opening- closing, thus reducing the risk of VILI [38, 39]. Con- versely, the deleterious e ects of high PEEP are increased end-inspiratory lung volume, hence increased risk of volutrauma , hemodynamic worsening linked to a decrease in preload, and above all to an increase in right ventricular afterload [40, 41]. When total PEEP is con- stant, the e ects of intrinsic PEEP are, during ARDS, identical to those of external PEEP [42, 43].
e extent of the bene cial and deleterious e ects of high PEEP varies greatly from one patient to another and
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 7 of 18
cannot be predicted from the simple clinical data avail- able at the bedside. However, studies using chest CT scans have shown that, on average, the amount of poten- tially recruitable lung tissue with high PEEP is greater when the PaO2/FiO2 ratio measured with a low PEEP (5 cmH2O) is low [44, 45].
A post hoc analysis of 2 randomized trials shows that, in patients in whom randomization led to increased PEEP, in-hospital mortality was lower for greater increases in the PaO2/FiO2 ratio after increase of PEEP .
Individually, the e ect of high PEEP in terms of recruit- ment cannot be assessed from changes in respiratory system compliance [45, 47]. No blood gas or respira- tory mechanics parameter easily available at the bedside allows quanti cation of the risk of volutrauma induced by the use of high PEEP. On average, the levels of PEEP used in randomized trials comparing “high” and “mod- erate” PEEP were, respectively, 15.1±3.6 cmH2O and 9.1 ± 2.7 cmH2O . us, 12 cmH2O can be consid- ered as the threshold above which PEEP can be quali ed as high.
No signi cant di erence in mortality was found in any of the 3 large randomized trials that compared the impact of high and moderate PEEP in ARDS patients ventilated with a tidal volume of 6 mL/kg PBW [37, 48, 49]. A meta- analysis of the individual data from patients included in these 3 trials showed that high PEEP was associated with a signi cant 5% reduction in hospital mortality in patients with moderate or severe ARDS (34.1% vs. 39.1%, p<.05), whereas it was associated with greater mortal- ity (27.2% vs. 19.4%, p=.07) in patients with mild ARDS .
In patients with moderate or severe ARDS, individual- ized PEEP setting using end-expiratory transpulmonary pressure did not result in a decrease in mortality com- pared to PEEP set using a PEEP/FiO2 scale .
High-frequency oscillation ventilation
R3.2. – High-frequency oscillation ventilation should not be used in ARDS patients.
parenchyma, whereas the sinusoidal oscillations of a membrane at a high respiratory rate (3–8 Hz) generate tidal volume. e gas ow and the in ation of a balloon valve allow adjustment of cPaw, which determines oxy- genation proportionally. Tidal volume increases with the amplitude of the membrane movements and decreases when the frequency increases, which explains why CO2 removal is inversely proportional to the frequency used.
Numerous physiological studies have suggested that HFOV is useful in the management of ARDS. anks to exchange mechanisms distinct from simple exchange by convection , HFOV enables a greater reduction in tidal volume and decreases the amplitude of cyclic vari- ations in transpulmonary pressure, thus allowing the use of a high cPaw so as to optimize lung recruitment. By increasing the proportion of parenchyma ventilated, the recruitment induced in HFOV may reduce lung stress and strain, reduce the sheer stress associated with the cyclic opening and closing of unstable alveoli, and limit VILI. Hence, the ventilation characteristics in HFOV make it theoretically ideal in terms of lung protection [52, 54].
Several clinical studies have reported that HFOV improves oxygenation in adults with ARDS and refractory hypoxemia in conventional ventilation [55–58]. ree randomized studies reported a tendency to decreased mortality when HFOV was used as an initial mode of ven- tilation in 58, 148 and 125 ARDS patients, respectively [59–61]. However, the use of excessive tidal volume in the control group limits the value of these studies, which do not allow recommendation of HFOV as the main mode of ventilation for ARDS. Recently, 2 large randomized trials found no bene t of HFOV compared with conventional mechanical ventilation with tidal volume = 6 mL/kg, limi- tation of plateau pressure, and PEEP adapted as a function of ARDS severity [62, 63]. In the OSCILLATE study, an aggressive recruitment strategy in HFOV was even associ- ated with a signi cant rise in mortality . It is possible that the use of a high cPaw induced overdistension without increasing aeration in alveolar collapse or ooding, in par- ticular in patients presenting heterogeneous lesions and a limited percentage of recruitable parenchyma. e use of high pressures may also have induced an increase in right ventricular afterload, right ventricular insu ciency ,andhemodynamicinstabilityrequiringhigherdoses of vasopressors . With a cPaw titration strategy based on the mean alveolar pressure used before the initiation of HFOV and the response in terms of oxygenation, Young et al. found no di erence in mortality in the OSCAR study when HFOV was compared with conventional
GRADE 1 −, STRONG AGREEMENT
High-frequency oscillation ventilation (HFOV) is an unconventional mode of ventilation proposed to improve gas exchange while protecting against VILI using a tidal volume below or equal to the anatomical dead space . Continuous gas ow creates a continuous distend- ing airway pressure (cPaw) so as to recruit the pulmonary
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 8 of 18
mechanical ventilation in ARDS patients . In 2016, the LUNG SAFE study revealed that HFOV was used in 1.2% of ARDS patients .
Several systematic meta-analyses of 5 randomized stud- ies evaluated secondary endpoints, such as gas exchange and the incidence of barotrauma [65–68]. ey did not show signi cant improvement in gas exchange or reduc- tion in barotrauma with HFOV. A recent meta-analysis of individual data suggests that HFOV may improve sur- vival in patients with more severe hypoxemia . e ideal modalities for cPaw titration, oscillation frequency, and monitoring of HFOV are poorly de ned. In particu- lar, studies are needed to determine whether evaluation of transpulmonary pressure by measurement of esopha- geal pressure is useful in regulating cPaw, improving lung recruitment, and avoiding overdistension . Pending the results of an ongoing study that is testing this hypoth- esis (Clinical Trials.gov NCT02342756), HFOV should be limited to clinical trials in patients with severe ARDS in whom conventional mechanical ventilation has failed despite prone positioning, and should be performed in centers with considerable experience of HFOV.
R3.3 – Recruitment maneuvers should probably not be used routinely in ARDS patients.
compliance [75–77]. By application of a high intra-alveo- lar pressure, they may run the risk of barotrauma related to overdistension of alveoli. By increasing intrathoracic pressure, they can reduce peripheral venous return and right ventricular preload, thereby inducing or worsening hemodynamic instability (particularly in hypovolemic patients) .
Recruitment maneuvers were evaluated in 8 con- trolled randomized studies [21, 35, 49, 78–82] in a total of 2735 patients between 1998 and 2018. e nature of the maneuvers used and the target airway pressures during the maneuver di ered substantially between studies. Four of the 8 studies recommended application of a continu- ous positive airway pressure of 40 cmH2O for 40 s [21, 49, 80, 82]. Seven of the 8 studies combined the recruitment maneuver with application of a high PEEP, with the aim of keeping recruited alveoli open [21, 35, 49, 78–81].
In the 8 studies, the use of recruitment maneuvers was not signi cantly associated with a reduction in mortal- ity at day 28 (RR = 0.89—95% CI [0.89–1.07]). In the only study without co-intervention, recruitment maneuvers were associated with reduced mortality (110 patients, RR=0.81—95% CI [0.69–0.95]). In each of the 7 stud- ies (2625 patients) that gave the PaO2/FiO2 ratio at day 1, it was signi cantly higher in the patients managed using a recruitment maneuver (average of the averages: 205.9 mmHg vs. 158.3 mmHg) [21, 35, 49, 78–81]. is improvement in PaO2/FiO2 persisted till day 77 (aver- age of the averages: 231.2 mmHg vs. 195.1 mmHg) in the same 7 studies (2625 patients) [21, 35, 49, 78–81]. ere was no evidence that a recruitment maneuver increased the risk of barotrauma (RR=1.25—95% CI [0.93–1.67]) in 6 studies [21, 35, 49, 78, 80, 81]. In contrast, there was signi cantly greater worsening of hemodynamic status (RR = 1.22—95% CI [1.04–1.45]) [35, 81].
ere is as yet no proven optimal recruitment maneu- ver, notably to minimize hemodynamic risk and the risk of barotrauma, while preserving e cacy in terms of lung oxygenation. A recent study  opens up a new possibil- ity by adapting the indication for a recruitment maneu- ver to the CT scan ndings (di use or focal) in ARDS. e search for a better target population among ARDS patients could provide new information concerning the e ect of recruitment maneuvers on mortality.
Area 4: Spontaneous ventilation
Early and short neuromuscular blockade
R4.1 – A neuromuscular blocking agent should probably be considered in ARDS patients with a PaO2/FiO2 ratio<150 mmHg to reduce mortal- ity. e neuromuscular blocking agent should be administered by continuous infusion early
GRADE 2 −, STRONG AGREEMENT
In cases of clear derecruitment (endotracheal aspira- tion, accidental or planned disconnection, intubation…), use can be made of a careful recruitment maneuver. If hypoxemia is refractory (PaO2/FiO2 < 100 mmHg) despite optimization of therapy, a recruitment maneuver can be envisaged in the absence of contraindication.
ere is no preferred recruitment maneuver. e recom- mended procedure should last no longer than 10–20 s, and the airway pressure should not exceed 30–40 cmH2O. e recruitment maneuver should be performed with care and should be interrupted if hemodynamic safety is poor.
ARDS patients frequently present pulmonary atelec- tasis, which decreases the ventilated lung volume, wors- ens hypoxemia, and increases VILI . e recruitment maneuver, by the application of a transiently high airway pressure, is intended to expand the collapsed lung so as to increase the number of alveolar units participating in gas exchange .
Several di erent maneuvers are used, such as the appli- cation of a continuous positive pressure (30–40 cmH2O) for 30–40 s, or the progressive increase of PEEP at con- stant driving pressure, or the progressive increase of driving pressure at constant PEEP [72–74]. Recruit- ment maneuvers improve oxygenation and dynamic
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 9 of 18
(within 48 h after the start of ARDS), for no more than 48 h, with at least daily evaluation.
routine spontaneous ventilation in the acute
GRADE 2 +, STRONG AGREEMENT
ree randomized trials tested the e ect of the addi- tion of a neuromuscular blocking agent to deep seda- tion at the initial phase of ARDS [83–85]. e primary outcome of only one of these trials was mortality . A randomized open trial (Reevaluation of Systemic Early Neuromuscular Blockade [ROSE]) methodologically slightly di erent is currently being analyzed . e ACURASYS study  included 339 patients present- ing with ARDS with a progression of less than 48 h and with a PaO2/FiO2 ratio<150 mmHg, PEEP≥5 cmH2O, and tidal volume from 6 to 8 mL/kg PBW in a double- blind, placebo-controlled multicenter study. Patients were included after optimizing invasive mechanical ventilation. Cisatracurium besylate was the neuromus- cular blocking agent used. e 90-day mortality did not di er between patients treated with cisatracurium and those treated with placebo (31.6% vs. 40.7%, respectively; p=0.08). However, the hazard ratio for 90-day mortality in the cisatracurium group was 0.68 (95% CI 0.48–0.98; p=0.04), after adjustment for the PaO2/FiO2 ratio, pla- teau pressure, and the Simpli ed Acute Physiology II score at inclusion . ere was improved survival in the patients with a PaO2/FiO2 ratio<120 mmHg. ere were more days alive and free of mechanical ventilation at day 90 in the cisatracurium group (HR 1.41; p=0.01), and there was no between-group di erence in the rate of intensive care unit-acquired paresis .
Oxygenation (PaO2/FiO2) increases when neuromuscu- lar blocking agents are used in ARDS patients [83, 84, 87, 88].
In a retrospective study, cisatracurium was not supe- rior to atracurium . In contrast, the duration of mechanical ventilation and the length of ICU stay were slightly but signi cantly shorter in patients with or at risk of ARDS who were treated with cisatracurium, compared with those treated with vecuronium .
e depth of neuromuscular block required is unknown. e ACURASYS study used high dosages of cisatracurium (37 mg/h) .
Neuromuscular blocking agents could have bene cial e ects in limiting expiratory e orts and Pendelluft e ect, and in increasing expiratory transpulmonary pressure .
Early spontaneous ventilation
R4.2.1 – Available data do not allow a recom- mendation to be made regarding a strategy of
phase of ARDS.
R4.2.2 – After the acute phase of ARDS, the experts suggest that ventilation with a pressure mode allowing spontaneous ventilation can be used when ensuring that the tidal volume gen- erated is close to 6 mL/kg PBW and does not exceed 8 mL/kg PBW.
e term spontaneous breathing refers to the activity of the respiratory muscles, which is responsible for spon- taneous ventilation (SV) in the ventilated patient. e importance of SV depends on the intensity of the breath- ing e orts and on the impedance of the respiratory sys- tem . Spontaneous breathing e orts are present in most ventilated patients, except for those in so-called controlled ventilation who are paralyzed and/or deeply sedated. Spontaneous breathing has very di erent con- sequences depending on the mode of ventilation used . During assisted controlled ventilation (either pres- sure or volume regulated), breathing e orts tend to increase minute ventilation by triggering (via the inspira- tory trigger) the ventilator. In this setting, tidal volume can worsen lung injury (concept of patient self-in icted lung injury) . e interaction can be more complex and responsible for patient-ventilator asynchrony, which in some cases increases tidal volume and may worsen the prognosis [94, 95]. Asynchrony can be limited by adapt- ing the ventilator settings or abolished by neuromuscular blocking agents administration.
With speci c pressure-controlled ventilation modes, which does not o er the possibility of inspiratory syn- chronization (absence of trigger as in airway pressure release ventilation or APRV), breathing e orts generate SV, which is superimposed on mechanical ventilation cycles . Spontaneous breathing e orts have ben- e cial e ects (improved oxygenation, alveolar recruit- ment, prevention of ventilation-induced diaphragmatic lesions), which should be balanced with deleterious e ects (increase in transpulmonary pressure and tidal volume, pendelluft, increased transvascular pressure of the vessels in the lung interstitium, and risk of pulmo- nary edema) . e bene t-risk balance depends on the severity of respiratory disease and on the level of SV . SV above 30 or 50% of the total minute ventilation is possibly harmful. If the ventilation de ned by the ventila- tor settings is increased and/or if sedation is too deep, SV
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 10 of 18
tends to decline. Conversely, SV increases if the ventila- tion set on the ventilator is insu cient and/or if sedation is insu cient or in cases of metabolic acidosis .
SV can be modulated by sedation and by the level of ventilation delivered by the ventilator.
Nonsynchronized pressure-controlled ventilation (like APRV) favors SV by limiting the asynchrony observed withpressure-orvolume-controlledassistedventilation. SV associated with nonsynchronized pressure-controlled ventilation (like APRV) is associated with increased res- piratory e ort, which can be detected by variations in airway occlusion pressure.
e bene cial e ect of SV on oxygenation and respira- tory mechanics has been demonstrated in animal mod- els and con rmed by clinical studies in small numbers of patients. A single-center randomized study comparing SV in APRV versus pressure-controlled ventilation (seda- tion and neuromuscular block) in 30 mechanically ven- tilated patients with multiple trauma showed a favorable e ect of SV on gas exchange, respiratory mechanics, and the duration of ventilation . e sedation strategy, the large between-group di erence in ventilation modalities, and the small number of patients prevent conclusions being drawn regarding the bene t of SV. ese methodo- logical obstacles are found in most studies assessing the bene t of SV.
In a recent, randomized single-center trial in 138 patients ventilated for at least 48 h with a PaO2/FiO2 ratio<250 mmHg, a protective ventilation strategy (6 mL/kg PBW, plateau pressure<30 cmH2O, PEEP guided by the PEEP-FiO2 table according to the ARD- SNet Protocol) was compared with APRV (tidal vol- ume 6 mL/kg PBW, plateau pressure<30 cmH2O, PEEP 5 cmH2O) designed to encourage SV . e sedation strategy was common to the two study arms. e number of days without ventilation at day 28 (principal endpoint) was signi cantly greater in the APRV arm. Likewise, compliance and oxygenation parameters were signi – cantly improved in APRV, while there was less sedation requirement . Tidal volume and driving pressure were comparable in the two arms, while PEEP and pla- teau pressure were signi cantly lower in APRV . e main limitations of this study are that it was single- center, there were few patients, and the experience of the “respiratory therapists” who adjusted the APRV settings, which are hard to master . Nonetheless, this study shows the feasibility of a strategy designed to reach mod- est levels of SV (approximately 30% of the minute ventila- tion). e complications were not more frequent in the APRV arm, in which the incidence of pneumothorax was low (4.2%) .
A nonsynchronized mode (like APRV) was com- pared (crossover, randomized physiological study) with
completely or partially synchronized pressure-controlled ventilation . Tidal volume and transpulmonary pres- sure were signi cantly lower in cases of nonsynchroniza- tion, whereas SV was associated with increased breathing e orts, which could be detected by monitoring airway occlusion pressure .
A randomized, controlled multicenter trial has com- pared the impact of ventilation that systematically encourages SV with assisted controlled ventilation, for a given strategy in the settings of tidal volume, end- inspiratory pressure, PEEP, sedation, weaning PEEP, and weaning ventilation. is trial (BiRDS) nished after the inclusion of 700 patients and the results are pending (www.clinicaltrials.gov NCT01862016). e study proto- col enabled adaptation of the level of sedation and venti- lation so as to achieve the aim of SV.
Area 5: Prone positioning
R5.1 – Prone positioning should be used in ARDS
patients with PaO /FIO ratio<150 mmHg to 22
reduce mortality. Sessions of at least 16 consecu- tive hours should be performed.
GRADE 1 +, STRONG AGREEMENT Rationale:
e use of prone positioning (PP) during ARDS has been studied in 8 randomized controlled trials, 5 of which were large [10, 45, 99–101] and 3 smaller [102–104]. e most recent meta-analysis concluded that there was no statistically signi cant di erence in mortality between the PP group and the supine position group . is meta-analysis included 3 sensitivity analyses on the role of protective ventilation, the duration of PP, and the severity of hypoxemia at the time of inclusion. When the trial protocol provided for protective mechanical ventila- tion, there was a non-signi cant reduction in mortality in favor of PP . is reduction in mortality was signi – cant for PP lasting longer than 12 h, but it not for shorter PP sessions . e reduction in mortality in favor of PP was signi cant for the most hypoxemic patients with moderate to severe ARDS, but was not signi cant for less hypoxemic patients (mild ARDS).
e PROSEVA study  done in 27 intensive care units showed a signi cant reduction in mortality in ARDS patients included after a 12- to 24-h stabilization period with a PaO2/FIO2 ratio<150 mmHg associated with PEEP of at least 5 cmH2O, an FIO2 of at least 60%, and tidal volume of 6 mL/kg PBW. is con rmed a pre- vious meta-analysis on individual data . In the PRO- SEVA trial PP group, the patients had on average 4 PP sessions of 17 consecutive hours (the protocol planned
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 11 of 18
sessions of at least 16 h). PP was continued even in the absence of improved oxygenation.
PP is inexpensive and simple to implement. Optimi- zation of the safety of PP requires that each department has a written procedure and speci c training of nursing teams.
Area 6: Extracorporeal gas exchange
Venovenous extracorporeal membrane oxygenation
R6.1 – Venovenous extracorporeal membrane oxygenation (ECMO) should probably be con- sidered in cases of severe ARDS with PaO2/ FiO2<80 mmHg and/or when mechanical ven- tilation becomes dangerous because of the increase in plateau pressure and despite opti- mization of ARDS management including high PEEP, neuromuscular blocking agents, and prone positioning. e decision to use ECMO should be evaluated early by means of contact with an expert center.
of them had prolonged sessions of PP. Sixty-day mortal- ity was 11% lower in the ECMO group (35% versus 46%), though the di erence did not reach statistical signi cance (p=0.09) . In contrast, the risk of treatment failure at day 90 (death in the ECMO group, death or crossover to ECMO in the control group) was signi cantly higher in the control group . Complications associated with ECMO were infrequent, and fewer cases of stroke were observed in the ECMO group. Salvage ECMO was used in 28% of control patients because of refractory hypox- emia . ese patients were extremely ill, and their clinical state deteriorated rapidly in the hours before ini- tiation of ECMO. eir mortality was 57% and 6 required venoarterial ECMO while undergoing cardiopulmonary resuscitation .
Although the frequentist analysis of this study is nega- tive in a strictly statistical sense (60-day mortality, 35% vs 46%, p=0.09), a post hoc Bayesian analysis of EOLIA  with various assumptions of prior belief and knowl- edge about ECMO e cacy in ARDS has shown that the posterior probability of a mortality reduction with ECMO as in the EOLIA trial, was very high (between 88 and 99%). Furthermore, the EOLIA trial showed that ECMO was safe when provided in high-volume expert centers . It allows the application of ultraprotective ventilation in which pressures and volumes generated by the respirator are drastically reduced, thus protect- ing the lung from further ventilation-induced lung injury. e EOLIA trial has also demonstrated the relevance and e cacy of hospital networks to safely retrieve on ECMO the most severely ill patients 24/7 with an ECMO mobile team to an ECMO referral center .
Low- ow extracorporeal CO2 removal
R6.2 – Available data do not allow a recommen- dation to be made concerning the use of low- ow extracorporeal CO2 removal during ARDS.
Arteriovenous or venovenous low- ow extracorporeal CO2 removal (ECCO2R) allows so-called “ultraprotec- tive” ventilation strategies (tidal volume<6 mL/kg PBW and decrease in plateau and driving pressures and in respiratory rate) during ARDS, by controlling hypercap- nia induced by the reduction in minute ventilation. Ten studies tested this approach [112–121], but the overall level of proof is very low. In the only recent randomized controlled trial that included 79 patients, the numbers of ventilator-free days at day 60 were not di erent between control and ECCO2R groups, although a post hoc analysis suggested a bene t of ECCO2R for the most hypoxemic patients (PaO2/FiO2 < 150 mmHg at inclusion) .
GRADE 2 +, STRONG AGREEMENT
Few studies have assessed the e cacy of ECMO in ARDS. e multicenter CESAR trial  randomized 180 patients to transfer to an ECMO center for consider- ation for ECMO or to conventional ventilatory support. e primary outcome of death and/or severe disability at 6 months was signi cantly less frequent in the ECMO group, but its interpretation is limited by a large number of control patients who did not receive protective ventila- tion, and by the fact that 25% of the patients randomized to the transfer and consideration for ECMO group did not actually receive ECMO .
Two retrospective case-controlled studies using pro- pensity score matching [108, 109] suggested a bene t of transferring patients with A(H1N1)-related ARDS dur- ing the 2009 in uenza pandemic to an expert venovenous ECMO referral center.
e randomized EOLIA trial  evaluated the e ect of early initiation of venovenous ECMO in severe ARDS while avoiding the methodological biases of CESAR. is multicenter trial included 249 patients with severe ARDS on mechanical ventilation for less than 7 days. Patients randomized to the early ECMO group received immedi- ate percutaneous venovenous cannulation while control group patients were managed with protocolized con- ventional mechanical ventilation. At inclusion, the aver- age PaO2/FiO2 ratio was 72, the SOFA score was above 10, and 75% of the patients were receiving vasopressors . It should be noted that all control group patients received neuromuscular blocking agents and that 90%
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 12 of 18
Observational studies suggest that hypercapnia has an unfavorable prognostic e ect in ARDS; it is associ- ated in multivariate analysis with pulmonary vascular and right ventricular dysfunction  and with mortal- ity . ECCO2R can decrease PaCO2 in hypercapnic ARDS patients receiving “conventional” protective venti- lation (tidal volume about 6 mL/kg PBW) [112, 115, 116, 122–124] or ultraprotective ventilation [117, 120]. None- theless, the positive e ect of the control of hypercapnia on morbidity and mortality has yet to be demonstrated in ARDS.
e e ect of ECCO2R on PaO2 in ARDS patients is inconstant, some studies reporting an improvement [119–122] and many others no signi cant e ect [112, 114, 115, 117, 118, 124, 125]. Because ECCO2R only pro- vides marginal blood oxygenation, venovenous ECMO is required in the most hypoxemic patients. Lastly, ECCO2R is associated with a wide range of complications (bleed- ing, thrombosis, and infections) that should be balanced against its potential bene ts .
Area 7: Inhaled nitric oxide
R7.1 – e experts suggest that inhaled nitric oxide can be used in cases of ARDS with deep hypoxemia despite the implementation of a pro- tective ventilation strategy and prone position- ing, and before envisaging use of venovenous
ECMO. EXPERT OPINION Rationale:
Initially considered as a pollutant, nitric oxide (NO) is a ubiquitous, odorless and colorless gas whose properties were demonstrated by Furchgott, Ignarro, Murad, and Moncada in work that was rewarded by a Nobel Prize . Produced by endothelial cells, NO induces vaso- dilation by increasing the level of cyclic GMP in smooth muscle cells. Depending on its concentration, NO, in addition to its vasomotor properties, produces numerous potentially interesting pro- or anti-in ammatory e ects in the setting of ARDS . Notably, it attenuates leu- kocyte activation and in ammatory responses, reduces platelet aggregation, has a bronchodilator e ect, and facilitates the production of surfactant.
When inhaled, NO di uses into ventilated areas where it induces vasodilation before rapidly binding to hemo- globin by a reaction with the ferrous and ferric ion of heme to form nitrosylated hemoglobin . By react- ing with oxyhemoglobin, the predominant form in the lung, NO forms methemoglobin and nitrates and does not result in systemic vasodilation. Approximately 70% of inhaled NO (iNO) is eliminated in the form of nitrate in
urine . iNO is a selective pulmonary arterial vaso- dilator likely to improve gas exchange by reducing the shunt and to control pulmonary arterial hypertension and right ventricular insu ciency, which has an unfa- vorable prognosis in ARDS [130, 131]. In addition, its e ects on platelets and leukocytes could prove of thera- peutic value in ARDS.
Inhalation of NO dilates the pulmonary vessels in ven- tilated areas and improves the ventilation-perfusion ratio by preferentially redistributing the blood ow to these areas. Eleven randomized trials report an improvement in the PaO2/FiO2 ratio after 24 h of treatment . However, this improvement is transient and only an anal- ysis based on 4 trials indicates improvement that persists after 96 h of treatment . Note that the response is greater if there is pulmonary arterial hypertension, that the concentrations likely to improve oxygenation are generally below 5 parts per million (ppm) , and that concentrations above 10 ppm are sometimes associated with a worsening of the PaO2/FiO2 ratio, possibly because of the di usion of NO into unventilated areas .
To date, 8 randomized studies in a total of 1025 adults with ARDS, including at least 10 treated with iNO, evaluated the impact of this treatment on mortality [133, 135–140]. None of these studies found signi cant improvement in survival at 28 days or long term. Analy- sis of available randomized studies reveals that iNO does not change the duration of mechanical ventilation, the time spent in intensive care, or the onset of barotrauma complications. Published between 1997 and 2004, most of these studies have a relatively modest risk of bias, but they su er from a certain number of methodologi- cal problems that complicate the interpretation. Most of these studies lack power and evaluate the response of heterogenous patients in terms of the etiology of ARDS. e modalities of administration (concentration, dura- tion, evaluation of the response, weaning) and of moni- toring were insu ciently de ned and varied greatly from one study to another. Also, these studies were conducted before the generalization of protective ventilation strate- gies for ARDS. In the most recent study, in 385 patients, the tidal volume used in the 2 groups was 10 mL/kg . Compliance with a protective ventilation strategy is not reported in any study, and there were no protocols for mechanical ventilation weaning or for optimization of sedation in these studies. It is therefore di cult to draw de nitive conclusions as to any bene t of iNO in ARDS.
Given a quite favorable bene t-risk ratio, the physi- ological e ects of iNO on the reduction in the intrapul- monary shunt, and the improvement of gas exchange, right ventricular performance, and cardiac ow may jus- tify its use in severe ARDS when PP and optimization of mechanical ventilation do not correct hypoxemia. Data
Papazian et al. Ann. Intensive Care
Page 13 of 18
Table 2 Summary of guidelines
Evaluation of ARDS management
Tidal volume adjustment
Positive end‐expiratory pressure R3.1.1
High‐frequency oscillation ventilation R3.2
Early and short neuromuscular blockade
Early spontaneous ventilation
The experts suggest that the e cacy and safety of all ventilation parameters and therapeutics associated with ARDS management should be evaluated at least every 24 h
A tidal volume around 6 mL/kg of predicted body weight (PBW) should be used as a rst approach in patients with recognized ARDS, in the absence of severe metabolic acidosis, including those with mild ARDS, to reduce mortality
The experts suggest a similar approach for all patients on invasive mechani‐ cal ventilation and under sedation in ICU, given the high rate of failure to recognize ARDS and the importance of rapidly implementing pulmonary protection
Once tidal volume is set to around 6 mL/kg predicted body weight, plateau pressure should be monitored continuously and should not exceed
30 cmH2O to reduce mortality
The experts suggest that tidal volume should not be increased when the plateau pressure is well below 30 cmH2O, except in cases of marked, persistent hypercapnia despite reduction in instrumental dead space and increase of respiratory rate
Available data do not allow a recommendation to be made regarding respi‐ rator settings based solely on limitation of driving pressure. This limitation can be envisaged as a complement to limitation of plateau pressure in some special instances
PEEP is an essential component of the management of ARDS and the experts suggest using a value above 5 cmH2O in all patients presenting with ARDS
High PEEP should probably be used in patients with moderate or severe ARDS, but not in patients with mild ARDS
The experts suggest reserving high PEEP for patients in whom it improves oxygenation without marked deterioration of respiratory system compli‐ ance or hemodynamic status. PEEP settings should be individualized
High‐frequency oscillation ventilation should not be used in ARDS patients
Recruitment maneuvers should probably not be used routinely in ARDS patients
A neuromuscular blocking agent should probably be considered in ARDS patients with a PaO2/FiO2 ratio < 150 mmHg to reduce mortality. The neu‐ romuscular blocking agent should be administered by continuous infusion early (within 48 h after the start of ARDS), for no more than 48 h, with at least daily evaluation
Available data do not allow a recommendation to be made regarding a strategy of routine spontaneous ventilation in the acute phase of ARDS
After the acute phase of ARDS, the experts suggest that ventilation with a pressure mode allowing spontaneous ventilation can be used when ensur‐ ing that the tidal volume generated is close to 6 mL/kg PBW and does not exceed 8 mL/kg PBW
Prone positioning should be used in ARDS patients with PaO2/FIO2
ratio < 150 mmHg to reduce mortality. Sessions of at least 16 consecutive hours should be performed
Level of proof
Grade 1+ Expert opinion
Grade 1 + Expert opinion
Grade 2 + Expert opinion
Grade 1 − Grade 2 −
Grade 2 +
No recommendation Expert opinion
Grade 1 +
￼ ￼ ￼ ￼ ￼ ￼ ￼
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 14 of 18
Venovenous extracorporeal membrane oxygenation
Low‐ ow extracorporeal CO2 removal R6.2
Inhaled nitrogen monoxide
Venovenous extracorporeal membrane oxygenation (ECMO) should prob‐ ably be considered in cases of severe ARDS with PaO2/FiO2 < 80 mmHg and/or when mechanical ventilation becomes dangerous because of the increase in plateau pressure and despite optimization of ARDS manage‐ ment including high PEEP, neuromuscular blocking agents, and prone positioning. The decision to use ECMO should be evaluated early by means of contact with an expert center
Available data do not allow a recommendation to be made concerning the use of low‐ ow extracorporeal CO2 removal during ARDS
The experts suggest that inhaled nitric oxide can be used in cases of ARDS with deep hypoxemia, despite the implementation of a protective ventilation strategy and prone positioning and before envisaging use of venovenous ECMO
Level of proof
Grade 2 +
No recommendation Expert opinion
￼ ￼ ￼ ￼ ￼ ￼ ￼
from physiological studies and the main clinical trials suggest that iNO has a good safety pro le and that its potential adverse e ects, notably methemoglobinemia, inhibition of platelet aggregation, and systemic vasodila- tion, are not clinically signi cant if a few precautions are observed [135, 141–143]. In the presence of oxygen, NO is transformed into nitrite (NO2) and then nitrate (NO3). However, if inhaled with a high FiO2, NO together with reactive oxygen species can form potentially toxic mol- ecules, in particular peroxynitrite (ONOO−) . NO can also bind to amino acids such as tyrosine and engen- der posttranslational changes in proteins, such as nitrosa- tion, nitrosylation, and nitration. Furthermore, a risk of renal toxicity has been described in a clinical trial  and in a recent meta-analysis . A systematic review of trials reveals that the risk of renal toxicity seems to be limited to ARDS patients exposed to high iNO concen- trations for prolonged periods . To limit the risk of complications with iNO, it is appropriate to: (1) minimize exposure by using systems of administration that enable inhalation synchronized with inspiratory ow and pre- cise monitoring of the concentrations of NO and NOx, (2) use the minimum e ective concentration to improve the PaO2/FiO2 ratio and not maintain iNO in a nonre- sponsive patient, (3) reevaluate the response and the required dosage daily. In cases of prolonged use, methe- moglobinemia should also be monitored. Lastly, weaning from iNO should be progressive so as to limit the risk of a sudden increase in pulmonary arterial pressure.
APRV: airway pressure release ventilation; ARDS: acute respiratory distress syndrome; cPaw: continuous distending airway pressure; ECMO: extracorpor‐ eal membrane oxygenation; ECCO2R: extracorporeal CO2 removal; GRADE: Grade of Recommendation Assessment, Development and Evaluation; HFOV:
high‐frequency oscillation ventilation; ICU: intensive care unit; NO: nitric oxide; PBW: predicted body weight; PEEP: positive end‐expiratory pressure; PICO: Patient Intervention Comparison Outcome; PP: prone position; PPM: parts per million; SRLF: Société de Réanimation de Langue Française; SV: spontaneous ventilation; VILI: ventilator‐induced lung injury.
Guidelines reviewed and endorsed by the SRLF (20/12/2018) boards.
LP proposed the elaboration of this recommendation and manuscript in agreement with the “Société de Réanimation de Langue Française” and wrote introduction; HF wrote the methodology section and gave the nal version with the nal presentation. CA and DR contributed to elaborate recommenda‐ tions and to write the rationale of area 1 (evaluation of ARDS management) and elaborated gures. LB, AVB, and DD contributed to elaborate recom‐ mendations and to write the rationale of area 2 (Tidal volume management). AM, JDC, and SJ contributed to elaborate recommendations and to write
the rationale of area 3 (alveolar recruitment). JMF and JCR contributed to elaborate recommendations and to write the rationale of area 4 (spontaneous ventilation). CG contributed to elaborate recommendations and to write the rationale of area 5 (prone positioning). AC and AMD contributed to elaborate recommendations and to write the rationale of area 6 (extracorporeal gas exchange). JDC contributed to elaborate recommendations and to write the rationale of area 7 (inhaled nitric oxide). LP and HF drafted the manuscript. All authors read and approved the nal manuscript.
This work was nancially supported by the Société de Réanimation de Langue Française (SRLF).
Availability of data and materials
Ethics approval and consent to participate
Consent for publication
Laurent Brochard: Philips; General Electric; Fisher Paykel; Air Liquide; Sentec; Medtronic Covidien. Jean‐Daniel Chiche: General Electric Healthcare. Alain Combes: Maquet Getinge; Baxter. Samir Jaber: Drager; Fisher Paykel; Xenios. Armand Mekontso‐Dessap: Air Liquide; Baxter; Fischer Paykel; Philips. Laurent Papazian: Air Liquide MS; MSD; Drager; Maquet; Medtronic. Jean‐Christophe M.
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 15 of 18
Richard: Air Liquide Medical System; Vygon; Covidien; General Electric. Damien Roux: Astellas. Antoine Vieillard‐Baron: GSK. The remaining authors declare no competing interests.
1 Service de Médecine Intensive ‐ Réanimation, Hôpital Nord, Chemin des Bourrely, 13015 Marseille, France. 2 Medical Intensive Care Unit, Centre Hos‐ pitalier Régional et Universitaire de Brest, site La Cavale Blanche, Bvd Tanguy Prigent, 29609 Brest Cedex, France. 3 Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada. 4 Service de Médecine Intensive ‐ Réanimation, Hôpital Cochin, Hôpitaux Universitaires Paris‐Centre, Assistance Publique ‐ Hôpitaux de Paris, 27 Rue du Faubourg Saint‐Jacques, 75014 Paris, France. 5 Service de Réanimation, Institut de Cardiologie, Groupe Hospitalier Pitié– Salpêtrière, Assistance Publique–Hôpitaux de Paris, 47, boulevard de l’Hôpital, 75013 Paris, France. 6 Intensive Care Unit, Louis Mourier Hospital, AP‐HP, 178 Rue des Renouillers, 92700 Colombes, France. 7 Service
de Réanimation Médicale, Hôpital De La Croix Rousse, Hospices Civils de Lyon, 103 Grande Rue de la Croix Rousse, 69004 Lyon, France. 8 Department of Anes‐ thesiology and Intensive Care (DAR B), Saint Eloi University Hospital, Montpel‐ lier, France. 9 Service de Réanimation Médicale, Hôpitaux Universitaires Henri‐ Mondor, AP‐HP, DHU A‐TVB, 94010 Créteil, France. 10 Medical Intensive Care Department, Angers University Hospital, 4, rue Larrey, 49933 Angers Cedex, France. 11 Emergency Department, General Hospital of Annecy, Annecy, France. 12 Hospital Ambroise Paré, Assistance Publique‐Hôpitaux de Paris, Boulogne, France. 13 Service de Médecine Intensive ‐ Réanimation, Centre Hospitalier Intercommunal Robert Ballanger, 93602 Aulnay‐sous‐Bois, France.
13. Dreyfuss D, Saumon G. Ventilator‐induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med. 1998;157(1):294–323.
14. Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med. 1990;16(6):372–7.
15. Slutsky AS. Mechanical ventilation. American College of Chest Physi‐ cians’ Consensus Conference. Chest. 1993;104(6):1833–59.
16. Webb HH, Tierney DF. Experimental pulmonary edema due to inter‐ mittent positive pressure ventilation with high in ation pressures. Protection by positive end‐expiratory pressure. Am Rev Respir Dis. 1974;110(5):556–65.
17. Brochard L, Roudot‐Thoraval F, Roupie E, Delclaux C, Chastre J, Fernandez‐Mondejar E, et al. Tidal volume reduction for prevention of ventilator‐induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med. 1998;158(6):1831–8.
18. Brower RG, Shanholtz CB, Fessler HE, Shade DM, White P Jr, Wiener CM, et al. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med. 1999;27(8):1492–8.
19. Nin N, Muriel A, Penuelas O, Brochard L, Lorente JA, Ferguson ND, et al. Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome. Intensive Care Med. 2017;43(2):200–8.
20. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301–8.
21. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi‐Filho G, et al. E ect of a protective‐ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):347–54.
22. Villar J, Kacmarek RM, Perez‐Mendez L, Aguirre‐Jaime A. A high positive end‐expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: a rand‐ omized, controlled trial. Crit Care Med. 2006;34(5):1311–8.
23. Burns KE, Adhikari NK, Slutsky AS, Guyatt GH, Villar J, Zhang H, et al. Pres‐ sure and volume limited ventilation for the ventilatory management of patients with acute lung injury: a systematic review and meta‐analysis. PLoS ONE. 2011;6(1):e14623.
24. Walkey AJ, Goligher EC, Del Sorbo L, Hodgson CL, Adhikari NKJ, Wunsch H, et al. Low tidal volume versus non‐volume‐limited strategies for patients with acute respiratory distress syndrome. A systematic review and meta‐analysis. Ann Am Thorac Soc. 2017;14(Supplement_4):S271–9.
25. Needham DM, Yang T, Dinglas VD, Mendez‐Tellez PA, Shanholtz C, Sevransky JE, et al. Timing of low tidal volume ventilation and intensive care unit mortality in acute respiratory distress syndrome. A prospective cohort study. Am J Respir Crit Care Med. 2015;191(2):177–85.
26. La ey JG, Bellani G, Pham T, Fan E, Madotto F, Bajwa EK, et al. Potentially modi able factors contributing to outcome from acute respira‐
tory distress syndrome: the LUNG SAFE study. Intensive Care Med. 2016;42(12):1865–76.
27. Villar J, Perez‐Mendez L, Basaldua S, Blanco J, Aguilar G, Toral D, et al. A risk tertiles model for predicting mortality in patients with acute res‐ piratory distress syndrome: age, plateau pressure, and P(aO(2))/F(IO(2)) at ARDS onset can predict mortality. Respir Care. 2011;56(4):420–8.
28. Chiumello D, Carlesso E, Cadringher P, Caironi P, Valenza F, Polli F, et al. Lung stress and strain during mechanical ventilation for acute respira‐ tory distress syndrome. Am J Respir Crit Care Med. 2008;178(4):346–55.
29. De Jong A, Cossic J, Verzilli D, Monet C, Carr J, Conseil M, et al. Impact of the driving pressure on mortality in obese and non‐obese ARDS patients: a retrospective study of 362 cases. Intensive Care Med. 2018;44(7):1106–14.
30. Stewart TE, Meade MO, Cook DJ, Granton JT, Hodder RV, Lapinsky SE, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pres‐ sure‐ and volume‐limited ventilation strategy group. N Engl J Med. 1998;338(6):355–61.
Received: 15 April 2019
Accepted: 27 May 2019
1. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute respiratory distress syndrome: the Berlin De nition. JAMA. 2012;307(23):2526–33.
2. Bellani G, La ey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epide‐ miology, patterns of care, and mortality for patients with acute respira‐ tory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788–800.
3. Li G, Malinchoc M, Cartin‐Ceba R, Venkata CV, Kor DJ, Peters SG, et al. Eight‐year trend of acute respiratory distress syndrome: a population‐ based study in Olmsted County, Minnesota. Am J Respir Crit Care Med. 2011;183(1):59–66.
4. Villar J, Blanco J, Anon JM, Santos‐Bouza A, Blanch L, Ambros A, et al. The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med. 2011;37(12):1932–41.
5. Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz‐Granados N, Cooper A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293–304.
6. De Prost N, Dreyfuss D. How to prevent ventilator‐induced lung injury? Minerva Anestesiol. 2012;78(9):1054–66.
7. Fan E, Brodie D, Slutsky AS. Acute respiratory distress syndrome: advances in diagnosis and treatment. JAMA. 2018;319(7):698–710.
8. Gattinoni L, Marini JJ, Collino F, Maiolo G, Rapetti F, Tonetti T, et al. The future of mechanical ventilation: lessons from the present and the past. Crit Care. 2017;21(1):183.
9. Cressoni M, Cadringher P, Chiurazzi C, Amini M, Gallazzi E, Marino A, et al. Lung inhomogeneity in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2014;189(2):149–58.
10. Guerin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159–68.
11. Chen L, Chen GQ, Shore K, Shklar O, Martins C, Devenyi B, et al. Imple‐ menting a bedside assessment of respiratory mechanics in patients with acute respiratory distress syndrome. Crit Care. 2017;21(1):84.
12. Ely EW, Baker AM, Evans GW, Haponik EF. The prognostic signi cance of passing a daily screen of weaning parameters. Intensive Care Med. 1999;25(6):581–7.
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 16 of 18
31. Hager DN, Krishnan JA, Hayden DL, Brower RG, Network ACT. Tidal volume reduction in patients with acute lung injury when plateau pres‐ sures are not high. Am J Respir Crit Care Med. 2005;172(10):1241–5.
32. Villar J, Martin‐Rodriguez C, Dominguez‐Berrot AM, Fernandez L, Ferrando C, Soler JA, et al. A quantile analysis of plateau and driving pressures: e ects on mortality in patients with acute respiratory distress syndrome receiving lung‐protective ventilation. Crit Care Med. 2017;45(5):843–50.
33. Amato MB, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372(8):747–55.
34. Guerin C, Papazian L, Reignier J, Ayzac L, Loundou A, Forel JM, et al. E ect of driving pressure on mortality in ARDS patients during lung protective mechanical ventilation in two randomized controlled trials. Crit Care. 2016;20(1):384.
35. Cavalcanti AB, Suzumura EA, Laranjeira LN, Paisani DM, Damiani LP, et al. E ect of lung recruitment and titrated positive end‐expiratory pressure (PEEP) vs low peep on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2017;318(14):1335–45.
36. Mekontso Dessap A, Boissier F, Charron C, Begot E, Repesse X, Legras A, et al. Acute cor pulmonale during protective ventilation for acute res‐ piratory distress syndrome: prevalence, predictors, and clinical impact. Intensive Care Med. 2016;42(5):862–70.
37. Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL, et al. Positive end‐expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646–55.
38. Sahetya SK, Goligher EC, Brower RG. Fifty years of research in ARDS. Setting positive end‐expiratory pressure in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;195(11):1429–38.
39. Slutsky AS, Ranieri VM. Ventilator‐induced lung injury. N Engl J Med. 2013;369(22):2126–36.
40. Fougeres E, Teboul JL, Richard C, Osman D, Chemla D, Monnet X. Hemodynamic impact of a positive end‐expiratory pressure setting in acute respiratory distress syndrome: importance of the volume status. Crit Care Med. 2010;38(3):802–7.
41. Schmitt JM, Vieillard‐Baron A, Augarde R, Prin S, Page B, Jardin F. Positive end‐expiratory pressure titration in acute respiratory distress syndrome patients: impact on right ventricular out ow impedance evaluated by pulmonary artery Doppler ow velocity measurements. Crit Care Med. 2001;29(6):1154–8.
42. Lessard MR, Guerot E, Lorino H, Lemaire F, Brochard L. E ects of pressure‐controlled with di erent I: E ratios versus volume‐controlled ventilation on respiratory mechanics, gas exchange, and hemodynam‐ ics in patients with adult respiratory distress syndrome. Anesthesiology. 1994;80(5):983–91.
43. Mercat A, Graini L, Teboul JL, Lenique F, Richard C. Cardiorespiratory e ects of pressure‐controlled ventilation with and without inverse ratio in the adult respiratory distress syndrome. Chest. 1993;104(3):871–5.
44. Caironi P, Carlesso E, Cressoni M, Chiumello D, Moerer O, Chiurazzi C, et al. Lung recruitability is better estimated according to the Berlin de nition of acute respiratory distress syndrome at standard 5 cm H2O rather than higher positive end‐expiratory pressure: a retrospective cohort study. Crit Care Med. 2015;43(4):781–90.
45. Gattinoni L, Caironi P, Cressoni M, Chiumello D, Ranieri VM, Quintel M, et al. Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006;354(17):1775–86.
46. Goligher EC, Kavanagh BP, Rubenfeld GD, Adhikari NK, Pinto R, Fan
E, et al. Oxygenation response to positive end‐expiratory pressure predicts mortality in acute respiratory distress syndrome. A second‐ ary analysis of the LOVS and ExPress trials. Am J Respir Crit Care Med. 2014;190(1):70–6.
47. Maggiore SM, Jonson B, Richard JC, Jaber S, Lemaire F, Brochard L. Alveolar derecruitment at decremental positive end‐expiratory pres‐ sure levels in acute lung injury: comparison with the lower in ection point, oxygenation, and compliance. Am J Respir Crit Care Med. 2001;164(5):795–801.
48. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukie‐ wicz M, et al. Higher versus lower positive end‐expiratory pressures in
patients with the acute respiratory distress syndrome. N Engl J Med.
49. Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, et al.
Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end‐expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):637–45.
50. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, et al. Higher vs lower positive end‐expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta‐analysis. JAMA. 2010;303(9):865–73.
51. Cavalcanti AB, Suzumura EA, Laranjeira LN, Paisani DM, Damiani LP, Guimaraes HP, et al. E ect of lung recruitment and titrated positive end‐ expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA. 2017;318(14):1335–45.
52. Ferguson ND, Villar J, Slutsky AS. Understanding high‐frequency oscillation: lessons from the animal kingdom. Intensive Care Med. 2007;33(8):1316–8.
53. Sklar MC, Fan E, Goligher EC. High‐frequency oscillatory ventilation in adults with ARDS: past, present, and future. Chest. 2017;152(6):1306–17.
54. Adhikari NK, Bashir A, Lamontagne F, Mehta S, Ferguson ND, Zhou Q, et al. High‐frequency oscillation in adults: a utilization review. Crit Care Med. 2011;39(12):2631–44.
55. Camporota L, Sherry T, Smith J, Lei K, McLuckie A, Beale R. Physiologi‐ cal predictors of survival during high‐frequency oscillatory ventila‐ tion in adults with acute respiratory distress syndrome. Crit Care. 2013;17(2):R40.
56. Fessler HE, Hager DN, Brower RG. Feasibility of very high‐frequency ventilation in adults with acute respiratory distress syndrome. Crit Care Med. 2008;36(4):1043–8.
57. Fort P, Farmer C, Westerman J, Johannigman J, Beninati W, Dolan S,
et al. High‐frequency oscillatory ventilation for adult respiratory distress syndrome—a pilot study. Crit Care Med. 1997;25(6):937–47.
58. Mehta S, Granton J, MacDonald RJ, Bowman D, Matte‐Martyn A, Bach‐ man T, et al. High‐frequency oscillatory ventilation in adults: the Toronto experience. Chest. 2004;126(2):518–27.
59. Bollen CW, van Well GT, Sherry T, Beale RJ, Shah S, Findlay G, et al. High frequency oscillatory ventilation compared with conventional mechan‐ ical ventilation in adult respiratory distress syndrome: a randomized controlled trial [ISRCTN24242669]. Crit Care. 2005;9(4):R430–9.
60. Derdak S, Mehta S, Stewart TE, Smith T, Rogers M, Buchman TG, et al. High‐frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled trial. Am J Respir Crit Care Med. 2002;166(6):801–8.
61. Mentzelopoulos SD, Malachias S, Kokkoris S, Roussos C, Zakynthinos SG. Comparison of high‐frequency oscillation and tracheal gas insu ation versus standard high‐frequency oscillation at two levels of tracheal pressure. Intensive Care Med. 2010;36(5):810–6.
62. Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, et al. High‐frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013;368(9):795–805.
63. Young D, Lamb SE, Shah S, MacKenzie I, Tunnicli e W, Lall R, et al. High‐ frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013;368(9):806–13.
64. Guervilly C, Forel JM, Hraiech S, Demory D, Allardet‐Servent J, Adda
M, et al. Right ventricular function during high‐frequency oscillatory ventilation in adults with acute respiratory distress syndrome. Crit Care Med. 2012;40(5):1539–45.
65. Gu XL, Wu GN, Yao YW, Shi DH, Song Y. Is high‐frequency oscillatory ventilation more e ective and safer than conventional protective ventilation in adult acute respiratory distress syndrome patients? A meta‐analysis of randomized controlled trials. Crit Care. 2014;18(3):R111.
66. Meade MO, Young D, Hanna S, Zhou Q, Bachman TE, Bollen C, et al. Severity of hypoxemia and e ect of high‐frequency oscillatory ventila‐ tion in acute respiratory distress syndrome. Am J Respir Crit Care Med. 2017;196(6):727–33.
67. Sud S, Sud M, Friedrich JO, Meade MO, Ferguson ND, Wunsch H, et al. High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): systematic review and meta‐ analysis. BMJ. 2010;340:c2327.
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 17 of 18
68. Sud S, Sud M, Friedrich JO, Wunsch H, Meade MO, Ferguson ND, et al. High‐frequency ventilation versus conventional ventilation for treat‐ ment of acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev. 2013;(2):CD004085.
69. Klapsing P, Moerer O, Wende C, Herrmann P, Quintel M, Bleckmann A, et al. High‐frequency oscillatory ventilation guided by transpulmonary pressure in acute respiratory syndrome: an experimental study in pigs. Crit Care. 2018;22(1):121.
70. Bendixen HH, Bullwinkel B, Hedley‐Whyte J, Laver MB. Atelectasis and shunting during spontaneous ventilation in anesthetized patients. Anesthesiology. 1964;25:297–301.
71. Borges JB, Okamoto VN, Matos GF, Caramez MP, Arantes PR, Barros F,
et al. Reversibility of lung collapse and hypoxemia in early acute respira‐ tory distress syndrome. Am J Respir Crit Care Med. 2006;174(3):268–78.
72. Constantin JM, Godet T, Jabaudon M, Bazin JE, Futier E. Recruitment maneuvers in acute respiratory distress syndrome. Ann Transl Med. 2017;5(14):290.
73. Fan E, Wilcox ME, Brower RG, Stewart TE, Mehta S, Lapinsky SE, et al. Recruitment maneuvers for acute lung injury: a systematic review. Am J Respir Crit Care Med. 2008;178(11):1156–63.
74. Godet T, Constantin JM, Jaber S, Futier E. How to monitor a recruitment maneuver at the bedside. Curr Opin Crit Care. 2015;21(3):253–8.
75. Almarakbi WA, Fawzi HM, Alhashemi JA. E ects of four intraoperative ventilatory strategies on respiratory compliance and gas exchange during laparoscopic gastric banding in obese patients. Br J Anaesth. 2009;102(6):862–8.
76. Schreiter D, Reske A, Stichert B, Seiwerts M, Bohm SH, Kloeppel R, et al. Alveolar recruitment in combination with su cient positive end‐ expiratory pressure increases oxygenation and lung aeration in patients with severe chest trauma. Crit Care Med. 2004;32(4):968–75.
77. Yang GH, Wang CY, Ning R. E ects of high positive end‐expiratory pressure combined with recruitment maneuvers in patients with acute respiratory distress syndrome. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2011;23(1):28–31.
78. Hodgson CL, Tuxen DV, Davies AR, Bailey MJ, Higgins AM, Holland AE, et al. A randomised controlled trial of an open lung strategy with staircase recruitment, titrated PEEP and targeted low airway pres‐ sures in patients with acute respiratory distress syndrome. Crit Care. 2011;15(3):R133.
79. Huh JW, Jung H, Choi HS, Hong SB, Lim CM, Koh Y. E cacy of posi‐ tive end‐expiratory pressure titration after the alveolar recruitment manoeuvre in patients with acute respiratory distress syndrome. Crit Care. 2009;13(1):R22.
80. Jabaudon M, Godet T, Futier E, Bazin JE, Sapin V, Roszyk L, et al. Ration‐ ale, study design and analysis plan of the lung imaging morphology for ventilator settings in acute respiratory distress syndrome study (LIVE study): study protocol for a randomised controlled trial. Anaesth Crit Care Pain Med. 2017;36(5):301–6.
81. Kacmarek RM, Villar J, Sulemanji D, Montiel R, Ferrando C, Blanco J, et al. Open lung approach for the acute respiratory distress syndrome: a pilot, randomized controlled trial. Crit Care Med. 2016;44(1):32–42.
82. Xi XM, Jiang L, Zhu B, Group RM. Clinical e cacy and safety of recruit‐ ment maneuver in patients with acute respiratory distress syndrome using low tidal volume ventilation: a multicenter randomized con‐ trolled clinical trial. Chin Med J (Engl). 2010;123(21):3100–5.
83. Forel JM, Roch A, Marin V, Michelet P, Demory D, Blache JL, et al. Neuro‐ muscular blocking agents decrease in ammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006;34(11):2749–57.
84. Gainnier M, Roch A, Forel JM, Thirion X, Arnal JM, Donati S, et al. E ect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2004;32(1):113–9.
85. Papazian L, Forel JM, Gacouin A, Penot‐Ragon C, Perrin G, Loundou A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107–16.
86. Huang DT, Angus DC, Moss M, Thompson BT, Ferguson ND, Ginde A, et al. Design and rationale of the reevaluation of systemic early neuro‐ muscular blockade trial for acute respiratory distress syndrome. Ann Am Thorac Soc. 2017;14(1):124–33.
87. Alhazzani W, Alshahrani M, Jaeschke R, Forel JM, Papazian L, Sevransky J, et al. Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta‐analysis of randomized con‐ trolled trials. Crit Care. 2013;17(2):R43.
88. Guervilly C, Bisbal M, Forel JM, Mechati M, Lehingue S, Bourenne J, et al. E ects of neuromuscular blockers on transpulmonary pressures in moderate to severe acute respiratory distress syndrome. Intensive Care Med. 2017;43(3):408–18.
89. Moore L, Kramer CJ, Delcoix‐Lopes S, Modrykamien AM. Compari‐ son of cisatracurium versus atracurium in early ARDS. Respir Care. 2017;62(7):947–52.
90. Sottile PD, Kiser TH, Burnham EL, Ho PM, Allen RR, Vandivier RW, et al. An observational study of the e cacy of cisatracurium compared with vecuronium in patients with or at risk for acute respiratory distress syndrome. Am J Respir Crit Care Med. 2018;197(7):897–904.
91. Yoshida T, Torsani V, Gomes S, De Santis RR, Beraldo MA, Costa EL, et al. Spontaneous e ort causes occult pendelluft during mechanical venti‐ lation. Am J Respir Crit Care Med. 2013;188(12):1420–7.
92. Richard JC, Lyazidi A, Akoumianaki E, Mortaza S, Cordioli RL, Lefebvre JC, et al. Potentially harmful e ects of inspiratory synchronization during pressure preset ventilation. Intensive Care Med. 2013;39(11):2003–10.
93. Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimize progression of lung injury in acute respiratory failure. Am J Respir Crit Care Med. 2017;195(4):438–42.
94. Blanch L, Villagra A, Sales B, Montanya J, Lucangelo U, Lujan M, et al. Asynchronies during mechanical ventilation are associated with mor‐ tality. Intensive Care Med. 2015;41(4):633–41.
95. Thille AW, Rodriguez P, Cabello B, Lellouche F, Brochard L. Patient‐venti‐ lator asynchrony during assisted mechanical ventilation. Intensive Care Med. 2006;32(10):1515–22.
96. Putensen C, Zech S, Wrigge H, Zinserling J, Stuber F, Von Spiegel T,
et al. Long‐term e ects of spontaneous breathing during ventilatory support in patients with acute lung injury. Am J Respir Crit Care Med. 2001;164(1):43–9.
97. Zhou Y, Jin X, Lv Y, Wang P, Yang Y, Liang G, et al. Early application
of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome. Intensive Care Med. 2017;43(11):1648–59.
98. Rittayamai N, Beloncle F, Goligher EC, Chen L, Mancebo J, Richard JM, et al. E ect of inspiratory synchronization during pressure‐controlled ventilation on lung distension and inspiratory e ort. Ann Intensive Care. 2017;7(1):100.
99. Guerin C, Gaillard S, Lemasson S, Ayzac L, Girard R, Beuret P, et al. E ects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial. JAMA. 2004;292(19):2379–87.
100. Mancebo J, Fernandez R, Blanch L, Rialp G, Gordo F, Ferrer M, et al. A multicenter trial of prolonged prone ventilation in severe acute respira‐ tory distress syndrome. Am J Respir Crit Care Med. 2006;173(11):1233–9.
101. Taccone P, Pesenti A, Latini R, Polli F, Vagginelli F, Mietto C, et al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2009;302(18):1977–84.
102. Chan MC, Hsu JY, Liu HH, Lee YL, Pong SC, Chang LY, et al. E ects of prone position on in ammatory markers in patients with ARDS due to community‐acquired pneumonia. J Formos Med Assoc. 2007;106(9):708–16.
103. Fernandez R, Trenchs X, Klamburg J, Castedo J, Serrano JM, Besso G, et al. Prone positioning in acute respiratory distress syndrome: a multicenter randomized clinical trial. Intensive Care Med. 2008;34(8):1487–91.
104. Voggenreiter G, Aufmkolk M, Stiletto RJ, Baacke MG, Waydhas C, Ose C, et al. Prone positioning improves oxygenation in post‐traumatic lung injury—a prospective randomized trial. J Trauma. 2005;59(2):333–41 (discussion 41–3).
105. Munshi L, Del Sorbo L, Adhikari NKJ, Hodgson CL, Wunsch H, Meade MO, et al. Prone position for acute respiratory distress syndrome.
A systematic review and meta‐analysis. Ann Am Thorac Soc. 2017;14(Supplement_4):S280–8.
106. Gattinoni L, Carlesso E, Taccone P, Polli F, Guerin C, Mancebo J. Prone positioning improves survival in severe ARDS: a pathophysiologic
Papazian et al. Ann. Intensive Care (2019) 9:69
Page 18 of 18
review and individual patient meta‐analysis. Minerva Anestesiol.
107. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM,
et al. E cacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):1351–63.
108. Noah MA, Peek GJ, Finney SJ, Gri ths MJ, Harrison DA, Grieve R, et al. Referral to an extracorporeal membrane oxygenation center and mortality among patients with severe 2009 in uenza A(H1N1). JAMA. 2011;306(15):1659–68.
109. Pham T, Combes A, Roze H, Chevret S, Mercat A, Roch A, et al. Extracorporeal membrane oxygenation for pandemic in uenza A(H1N1)‐induced acute respiratory distress syndrome: a cohort study and propensity‐matched analysis. Am J Respir Crit Care Med. 2013;187(3):276–85.
110. Combes A, Hajage D, Capellier G, Demoule A, Lavoue S, Guervilly C, et al. Extracorporeal membrane oxygenation for severe acute respira‐ tory distress syndrome. N Engl J Med. 2018;378(21):1965–75.
111. Goligher EC, Tomlinson G, Hajage D, Wijeysundera DN, Fan E, Juni P, et al. Extracorporeal membrane oxygenation for severe acute respira‐ tory distress syndrome and posterior probability of mortality bene t in a post hoc Bayesian analysis of a randomized clinical trial. JAMA. 2018;320(21):2251–9.
112. Allardet‐Servent J, Castanier M, Signouret T, Soundaravelou R, Lepidi A, Seghboyan JM. Safety and e cacy of combined extracorporeal CO2 removal and renal replacement therapy in patients with acute respira‐ tory distress syndrome and acute kidney injury: the pulmonary and renal support in acute respiratory distress syndrome study. Crit Care Med. 2015;43(12):2570–81.
113. Bein T, Weber‐Carstens S, Goldmann A, Muller T, Staudinger T, Brederlau J, et al. Lower tidal volume strategy (approximately 3 ml/kg) combined with extracorporeal CO2 removal versus ‘conventional’ protective venti‐ lation (6 ml/kg) in severe ARDS: the prospective randomized Xtravent‐ study. Intensive Care Med. 2013;39(5):847–56.
114. Fanelli V, Ranieri MV, Mancebo J, Moerer O, Quintel M, Morley S, et al. Feasibility and safety of low‐ ow extracorporeal carbon dioxide removal to facilitate ultra‐protective ventilation in patients with moder‐ ate acute respiratory distress sindrome. Crit Care. 2016;20:36.
115. Forster C, Schriewer J, John S, Eckardt KU, Willam C. Low‐ ow CO(2) removal integrated into a renal‐replacement circuit can reduce acidosis and decrease vasopressor requirements. Crit Care. 2013;17(4):R154.
116. Hermann A, Riss K, Schellongowski P, Bojic A, Wohlfarth P, Robak O,
et al. A novel pump‐driven veno‐venous gas exchange system during extracorporeal CO2‐removal. Intensive Care Med. 2015;41(10):1773–80.
117. Nierhaus A, Frings DP, Braune S, Baumann HJ, Schneider C, Wittenburg B, et al. Interventional lung assist enables lung protective mechanical ventilation in acute respiratory distress syndrome. Minerva Anestesiol. 2011;77(8):797–801.
118. Schmidt M, Jaber S, Zogheib E, Godet T, Capellier G, Combes A. Feasibil‐ ity and safety of low‐ ow extracorporeal CO2 removal managed with a renal replacement platform to enhance lung‐protective ventilation of patients with mild‐to‐moderate ARDS. Crit Care. 2018;22(1):122.
119. Winiszewski H, Aptel F, Belon F, Belin N, Chaignat C, Patry C, et al. Daily use of extracorporeal CO2 removal in a critical care unit: indications and results. J Intensive Care. 2018;6:36.
120. Zimmermann M, Bein T, Arlt M, Philipp A, Rupprecht L, Mueller T, et al. Pumpless extracorporeal interventional lung assist in patients with acute respiratory distress syndrome: a prospective pilot study. Crit Care. 2009;13(1):R10.
121. Terragni PP, Del Sorbo L, Mascia L, Urbino R, Martin EL, Birocco A, et al. Tidal volume lower than 6 ml/kg enhances lung protection: role of extracorporeal carbon dioxide removal. Anesthesiology. 2009;111(4):826–35.
122. Bein T, Weber F, Philipp A, Prasser C, Pfeifer M, Schmid FX, et al. A new pumpless extracorporeal interventional lung assist in critical hypox‐ emia/hypercapnia. Crit Care Med. 2006;34(5):1372–7.
123. Liebold A, Philipp A, Kaiser M, Merk J, Schmid FX, Birnbaum DE. Pump‐ less extracorporeal lung assist using an arterio‐venous shunt. Applica‐ tions and limitations. Minerva Anestesiol. 2002;68(5):387–91.
124. Munoz‐Bendix C, Beseoglu K, Kram R. Extracorporeal decarboxylation in patients with severe traumatic brain injury and ARDS enables e ective control of intracranial pressure. Crit Care. 2015;19:381.
125. Weber‐Carstens S, Bercker S, Hommel M, Deja M, MacGuill M, Dreykluft C, et al. Hypercapnia in late‐phase ALI/ARDS: providing spontaneous breathing using pumpless extracorporeal lung assist. Intensive Care Med. 2009;35(6):1100–5.
126. Taccone FS, Malfertheiner MV, Ferrari F, Di Nardo M, Swol J, Broman LM, et al. Extracorporeal CO2 removal in critically ill patients: a systematic review. Minerva Anestesiol. 2017;83(7):762–72.
127. Howlett R. Nobel award stirs up debate on nitric oxide breakthrough. Nature. 1998;395(6703):625–6.
128. Gri ths MJ, Evans TW. Inhaled nitric oxide therapy in adults. N Engl J Med. 2005;353(25):2683–95.
129. Wang X, Tanus‐Santos JE, Reiter CD, Dejam A, Shiva S, Smith RD, et al. Biological activity of nitric oxide in the plasmatic compartment. Proc Natl Acad Sci U S A. 2004;101(31):11477–82.
130. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vaso‐ constriction. Circulation. 1991;83(6):2038–47.
131. Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med. 1993;328(6):399–405.
132. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016;(6):CD002787.
133. Gerlach H, Keh D, Semmerow A, Busch T, Lewandowski K, Pappert DM, et al. Dose‐response characteristics during long‐term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Am J Respir Crit Care Med. 2003;167(7):1008–15.
134. Gerlach H, Pappert D, Lewandowski K, Rossaint R, Falke KJ. Long‐
term inhalation with evaluated low doses of nitric oxide for selective improvement of oxygenation in patients with adult respiratory distress syndrome. Intensive Care Med. 1993;19(8):443–9.
135. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, et al. E ects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998;26(1):15–23.
136. Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med. 1999;25(9):911–9.
137. Michael JR, Barton RG, Sa e JR, Mone M, Markewitz BA, Hillier K, et al. Inhaled nitric oxide versus conventional therapy: e ect on oxygenation in ARDS. Am J Respir Crit Care Med. 1998;157(5 Pt 1):1372–80.
138. Park KJ, Lee YJ, Oh YJ, Lee KS, Sheen SS, Hwang SC. Combined e ects of inhaled nitric oxide and a recruitment maneuver in patients with acute respiratory distress syndrome. Yonsei Med J. 2003;44(2):219–26.
139. Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K Jr, et al. Low‐dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004;291(13):1603–9.
140. Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Ducruet T, et al. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study. Am J Respir Crit Care Med. 1998;157(5 Pt 1):1483–8.
141. McMahon TJ, Moon RE, Luschinger BP, Carraway MS, Stone AE, Stolp BW, et al. Nitric oxide in the human respiratory cycle. Nat Med. 2002;8(7):711–7.
142. Troncy E, Francoeur M, Salazkin I, Yang F, Charbonneau M, Leclerc G, et al. Extra‐pulmonary e ects of inhaled nitric oxide in swine with and without phenylephrine. Br J Anaesth. 1997;79(5):631–40.
143. Weinberger B, Laskin DL, Heck DE, Laskin JD. The toxicology of inhaled nitric oxide. Toxicol Sci. 2001;59(1):5–16.
144. Ruan SY, Huang TM, Wu HY, Wu HD, Yu CJ, Lai MS. Inhaled nitric oxide therapy and risk of renal dysfunction: a systematic review and meta‐ analysis of randomized trials. Crit Care. 2015;19:137.
Springer Nature remains neutral with regard to jurisdictional claims in pub‐ lished maps and institutional a liations.