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I need help writing a full formal protocol for ARDS patients, I have this updated study to use as guidelines. I need it for my hospital as a protocol. I am a respiratory therapist Just need it to be in Protocol format, you got the points in the article and the guidelines. IN C LU S IO N C R IT E R IA : A cu te o n se t o f 1. Pa O 2/ Fi O 2 ≤ 30 0 (c or re ct ed f or a lt itu de ) 2. B ila te ra l ( pa tc hy , di ff u se , or h om og en eo u s) in fil tr at es c on si st en t w it h pu lm on ar y ed em a 3. N o cl in ic al e vi de nc e of le ft a tr ia l h yp er te ns io n P A R T I : V E N T IL A T O R S E T U P A N D A D JU S T M E N T 1. C al cu la te p re di ct ed b od y w ei gh t (P B W ) M a le s = 5 0 + 2 .3 [ he ig ht ( in ch es ) - 60 ] F e m a le s = 4 5. 5 + 2 .3 [ he ig ht ( in ch es ) -6 0] 2. Se le ct a n y ve n ti la to r m od e 3. Se t ve nt ila to r se tt in g s to a ch ie ve in it ia l V T = 8 m l/ kg P B W 4. R ed uc e V T b y 1 m l/ kg a t in te rv al s ≤ 2 ho ur s un ti l V T = 6 m l/ kg P B W . 5. Se t in it ia l r at e to a pp ro xi m at e ba se lin e m in u te v en ti la tio n (n ot > 3 5 bp m ). 6. A dj us t V T a nd R R t o ac hi ev e pH a nd p la te au p re ss ur e go al s be lo w . AA RR DD SS nn ee tt O X Y G E N A T IO N G O A L: P a O 2 5 5 -8 0 m m H g o r S p O 2 8 8 -9 5 % U se a m in im um P EE P of 5 c m H 2O . C on si de r u se o f in cr em en ta l F iO 2/ PE E P co m bi na tio ns s u ch a s sh ow n be lo w ( no t re qu ir ed ) to a ch ie ve g oa l. Lo w e r P E E P / h ig h e r F iO 2 F iO 2 0. 3 0. 4 0. 4 0. 5 0. 5 0. 6 0. 7 0. 7 P E E P 5 5 8 8 10 10 10 12 N IH N H LB I A R D S C lin ic al N et w or k F iO 2 0. 7 0. 8 0. 9 0. 9 0. 9 1. 0 P E E P 14 14 14 16 18 18 -2 4 M ec ha ni ca l V en ti la ti on P ro to co l S um m ar y H ig h e r P E E P / lo w e r F iO 2 F iO 2 0. 3 0. 3 0. 3 0. 3 0. 3 0. 4 0. 4 0. 5 P E E P 5 8 10 12 14 14 16 16 F iO 2 0. 5 0. 5- 0. 8 0. 8 0. 9 1. 0 1. 0 P E E P 18 20 22 22 22 24 __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ P LA T E A U P R E S S U R E G O A L : ≤ 3 0 c m H 2 O C he ck P pl at ( 0. 5 se co nd in sp ir at or y pa us e) , at le as t q 4h a nd a ft er e ac h ch an ge in P E E P or V T . If P p la t > 3 0 c m H 2 O : de cr ea se V T b y 1m l/ kg s te ps ( m in im um = 4 m l/ kg ). If P p la t < 2 5 c m H 2 O a n d V T < 6 m l/ k g , in cr ea se V T b y 1 m l/ kg u nt il Pp la t > 2 5 cm H 2O o r V T = 6 m l/ kg . If P p la t < 3 0 a n d b re a th s ta ck in g o r d y s- sy n ch ro n y o cc u rs : m ay in cr ea se V T in 1 m l/ kg in cr em en ts t o 7 or 8 m l/ kg if P pl at r em ai ns < 3 0 cm H 2O . __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ _ p H G O A L: 7 .3 0 -7 .4 5 A ci d o si s M a n a g e m e n t: ( p H < 7 .3 0 ) If p H 7 .1 5 -7 .3 0 : In cr ea se R R u nt il pH > 7 .3 0 or P aC O 2 < 2 5 (M ax im um s et R R = 3 5) . . If p H < 7 .1 5 : In cr ea se R R t o 35 . If p H r em ai ns < 7 .1 5, V T m ay b e in cr ea se d in 1 m l/ kg s te ps u nt il pH > 7. 15 ( Pp la t ta rg et o f 30 m ay b e ex ce ed ed ). M ay g iv e N aH C O 3 A lk a lo si s M a n a g e m e n t: ( p H > 7 .4 5 ) D ec re as e ve nt r at e if po ss ib le . __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ __ I: E R A T IO G O A L: R ec om m en d th at d ur at io n of in sp ir at io n be < du ra ti on o f ex pi ra tio n. P A R T I I: W E A N IN G A . C o n d u ct a S P O N T A N E O U S B R E A T H IN G T R IA L d a il y w h e n : 1. Fi O 2 ≤ 0. 40 a nd P E E P ≤ 8 O R F iO 2 < 0 .5 0 an d PE EP < 5 . 2. PE E P an d Fi O 2 ≤ va lu es o f pr ev io us d ay . 3. Pa ti en t ha s ac ce pt ab le s po n ta ne ou s br ea th in g ef fo rt s. ( M ay de cr ea se v en t ra te b y 50 % f or 5 m in u te s to d et ec t ef fo rt .) 4. Sy st ol ic B P ≥ 90 m m H g w ith ou t va so pr es so r su pp or t. 5. N o ne ur om us cu la r bl oc ki ng a ge nt s or b lo ck ad e. B . S P O N T A N E O U S B R E A T H IN G T R IA L (S B T ): If a ll a b o v e c ri te ri a a re m e t a n d s u b je ct h a s b e e n i n t h e s tu d y fo r a t le a st 1 2 h o u rs , in it ia te a t ri a l o f U P T O 1 2 0 m in u te s o f sp o n ta n e o u s b re a th in g w it h F iO 2 < 0 .5 a n d P E E P < 5 : 1. P la ce o n T -p ie ce , tr ac h co lla r, o r C PA P ≤ 5 cm H 2O w ith P S < 5 2. A ss es s fo r to le ra nc e as b el ow f or u p to t w o h ou rs . a. S pO 2 ≥ 90 : an d/ or P aO 2 ≥ 60 m m H g b. S po nt an eo u s V T ≥ 4 m l/ kg P B W c. R R ≤ 3 5/ m in d. p H ≥ 7 .3 e. N o re sp ir at or y di st re ss ( di st re ss = 2 o r m or e) ¾ H R > 1 20 % o f ba se lin e ¾ M ar ke d ac ce ss or y m us cl e u se ¾ A bd om in al p ar ad ox ¾ D ia ph or es is ¾ M ar ke d dy sp n ea 3. I f to le ra te d fo r at le as t 30 m in u te s, c on si de r ex tu ba tio n. 4. If n ot t ol er at ed r es um e pr e- w ea ni ng s et tin g s. D ef in iti on o f U N A S S IS T E D B R E A T H IN G (D if fe re n t fr o m t h e sp o n ta n eo u s b re at h in g cr it er ia a s P S is n o t al lo w ed ) 1. E xt ub at ed w ith fa ce m as k, n as al p ro ng o xy ge n, o r ro om a ir, O R 2. T -t ub e br ea th in g, O R 3. T ra ch eo st om y m as k br ea th in g, O R 4. C P A P le ss th an o r eq ua l t o 5 cm H 20 w it h o u t p re ss u re s u p p o rt o r IM V a ss is ta n ce . Papazian et al. Ann. Intensive Care (2019) 9:69 https://doi.org/10.1186/s13613-019-0540-9 R E V I E W Formal guidelines: management of acute respiratory distress syndrome 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 Abstract 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 effect, 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 classification 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. © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/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. Introduction Acute respiratory distress syndrome (ARDS) is an inflam- matory process in the lungs that induces non-hydrostatic protein-rich pulmonary oedema. The immediate conse- quences are profound hypoxemia, decreased lung com- pliance, and increased intrapulmonary shunt and dead space. The clinicopathological aspects include severe inflammatory injury to the alveolar-capillary barrier, sur- factant depletion, and loss of aerated lung tissue. The most recent definition of ARDS, the Berlin defi- nition, was proposed by a working group under the aegis of the European Society of Intensive Care Medi- cine [1]. It defines 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 (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. The Berlin defi- 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 [2]. 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 [2], was about 40%, and reached 45% in patients presenting with severe ARDS [2–4]. Significant physical, psychological, and cognitive sequelae, with a marked impact on quality of life, have been reported up to 5 years after ARDS [5]. Open Access *Correspondence: [email protected] 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 http://creativecommons.org/licenses/by/4.0/ http://crossmark.crossref.org/dialog/?doi=10.1186/s13613-019-0540-9&domain=pdf Page 2 of 18Papazian et al. Ann. Intensive Care (2019) 9:69 One of the most important results of the LUNG SAFE study was that ARDS was not identified as such by the primary care clinician in almost 40% of cases [2]. This was particularly so for mild ARDS, in which only 51% of cases were identified [2]. When all ARDS criteria were met, only 34% of ARDS patients were identified, suggest- ing that there was a delay in adapting the treatment, in particular mechanical ventilation [2]. This 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 [2]. Plateau pres- sure was measured in only 40% of ARDS patients [2]. 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) [2]. Analysis of the LUNG SAFE results also shows a lack of relation between PEEP and the PaO2/FIO2 ratio [2]. 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 [2]. The 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 [9]. ARDS is not a disease; it is a syndrome defined 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 effective in improving outcome. Minimizing VILI thus generally aims reducing volutrauma (reduction in global stress and strain). Low- ering airway pressures has the theoretical dual benefit of minimizing overdistension of the aerated areas and miti- gating negative hemodynamic consequences. The current SRLF guidelines are more than 20  years old and so there was a pressing need to update them. The main aim with these formal guidelines was voluntar- ily to limit the topics to the best studied fields, 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 insufficient assessment of their effects on prognosis (respiratory rate, mechanical power, target oxygenation, pH, PaCO2…). We also limited these guidelines to adult patients, to early phase of ARDS (first few days), and to invasive mechanical ventilation. Methods These guidelines have been formulated by an expert work- ing group selected by the SRLF. The organizing commit- tee first defined the questions to be addressed and then designated the experts in charge of each question. The questions were formulated according to a Patient Inter- vention Comparison Outcome (PICO) format after a first meeting of the expert group. The literature was analyzed using Grade of Recommendation Assessment, Develop- ment and Evaluation (GRADE) methodology. A level of proof was defined 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. The 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 insufficient, the question could be the subject of a recom- mendation in the form of an expert opinion (the experts suggest…). The 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). The 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 - The experts suggest that the efficacy and safety of all ventilation parameters and thera- peutics associated with ARDS management should be evaluated at least every 24 h. EXPERT OPINION Page 3 of 18Papazian et al. Ann. Intensive Care (2019) 9:69 Rationale: Evaluation of the efficacy 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 effi- 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- ficient response to first-line treatments. Figure 1 shows the treatments implemented to patients with ARDS based on the severity of respiratory distress. The decision to initiate some treatments is taken after a “stabilization” phase [10] that includes optimization of mechanical ventilation as the first step of management. Early evaluation of efficacy 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). The safety of drug therapies and procedures must also be regularly evaluated. These guidelines also address the Table 1 Recommendations according to the GRADE methodology Recommendations according to the GRADE methodology High level of proof Strong recommendation “…should be done…” Grade 1 + Moderate level of proof Optional recommendation “… should probably be done…” Grade 2 + Insufficient level of proof Recommendation in the form of an expert opinion “The experts suggest…” Expert opinion Moderate level of proof Optional recommendation “… should probably not be done…” Grade 2 − High level of proof Strong recommendation “…should not be done…” Grade 1 − Insufficient level of proof No recommendation Fig. 1 Therapeutic algorithm regarding early ARDS management (EXPERT OPINION) Page 4 of 18Papazian et al. Ann. Intensive Care (2019) 9:69 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 benefits 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 first 48  h) [11]. 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). These changes were associated with improvements in plateau pressure (− 2  cmH2O on aver- age), driving pressure (− 3 cmH2O on average), and oxy- genation index [11]. It is difficult to define 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 [12]. Nonetheless, more frequent assess- ment might be necessary and benefit 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 first 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 – The 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. EXPERT OPINION Rationale: 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 first. Too high a rate, however, engen- ders a risk of dynamic hyperinflation and also increases each minute cumulative exposure to potentially risky insufflation. A PaCO2 below 50  mmHg is generally acceptable. A reduction in instrumental dead space is also appropriate, and a heated humidifier should be used in first intention. The PBW should be calculated for each patient upon admission as a function of height and sex. The 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 effects 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 effects [19], 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 [20]. The 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 benefits of this treatment arm. A 25% reduction in the relative risk of mortality was observed, i.e., a 30–40% decrease in overall mortality. This study had an enormous impact on clinical practice. It was not the first 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 [21]. Other studies using the same approach as Amato et al. found a similar reduction in mortality [22]. Meta-analyses of tidal vol- ume reduction have often included rather heterogenous studies [23]. The most recent included seven randomized trials in 1481 patients [24] 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 significant relation between tidal volume reduc- tion and the mortality reduction effect. However, when the studies that combined high PEEP and low volumes were excluded, the effect of reduced tidal volume was just a non-significant trend (0.87 [0.70, 1.08]). Accord- ing to the authors, this suggests, but does not prove, that reduced tidal volumes significantly decrease mortality Page 5 of 18Papazian et al. Ann. Intensive Care (2019) 9:69 during ARDS. In an observational study, 11,558 ventila- tion parameters were available for 482 ARDS patients identified prospectively [25]. The 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% confidence interval, 1.06–1.44; p = 0.008) [25]. 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 first tidal volume was higher than the effect of the following volumes [25]. In the LUNG SAFE study [2], tidal volume did not seem to be a sig- nificant factor in mortality. However, the volume range was limited [26], 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. There was no difference in survival in the patients whose tidal volume was equal to or greater than the median value of 7.1 mL/kg PBW [26]. In addition, the use of lower tidal volumes in patients with severe ARDS may involve potentially confounding effects, which are difficult to analyze completely in purely observational data [26]. In all analyses, however, the pressures (peak pressure, plateau pressure, driving pressure, and PEEP) carried more significant weight than tidal volume in the prognosis [26]. Plateau pressure 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 - The 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. EXPERT OPINION Rationale: 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 [16], there is less lung injury with the same high plateau pres- sure when the tidal volume is reduced by means of tho- racic stiffness [13], a situation encountered in the very obese. The 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 [2]. An ancillary study of LUNG SAFE has shown that plateau pressure, which can be modified by the intensivist, is strongly and positively correlated with mortality [26]. A high plateau pressure is an independent mortality risk factor, as it reflects either great severity (associated with poor lung compliance) or inadequate mechanical ventilation [27]. The 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 reflection of lung distension [28]. This is particularly so in patients with abnormal compliance of the chest wall, and in some obese patients. The relation between plateau pressure and mortality or the risk of barotrauma is less clear in these patients [29], which may suggest tolerance of plateau pressure a little above 30  cmH2O, provided that the tidal volume is reduced to limit VILI [13]. 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 significant decrease in mortality in the group with limited volume and pressure was observed only in the 2 studies [20, 21] where differ- 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 [31]. In a recent study in 478 patients, a thresh- old plateau pressure of 29 cmH2O was identified beyond which hospital mortality increased [32]. Even in patients ventilated with a driving pressure below 19  cmH2O, a plateau pressure strictly below 30  cmH2O would enable a significant reduction in mortality, a greater effect than that of a driving pressure below 19  cmH2O when the plateau pressure is already below 30  cmH2O [32]. These results were validated in the same study in a different cohort of 300 patients [32]. Driving pressure Page 6 of 18Papazian et al. Ann. Intensive Care (2019) 9:69 R2.3 – Available data do not allow a recommen- dation to be made regarding respirator settings based solely on limitation of driving pressure. This limitation can be envisaged as a comple- ment to limitation of plateau pressure in some special instances. NO RECOMMENDATION Rationale: One study retrospectively evaluated the influence of driv- ing pressure on prognosis by means of a complex statis- tical analysis of nine randomized controlled studies of ventilation strategy (comparison of different values of tidal volume and PEEP, during ARDS) [33]. The 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. The same was true when the data of two studies showing improved survival during ARDS (by neuromuscular block and by prone positioning) were combined [34]. 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 [35] (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 [35]. Analysis of a series of mechanically ventilated ARDS patients presenting acute cor pulmonale [36] suggests that when the plateau pressure is kept sufficiently 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. This would therefore amount to comparing two levels of PEEP during ventilation with limited plateau pressure. This is exactly what the EXPRESS study did, and its results were negative [37]. In practical terms, it would be best first to measure and limit plateau pressure, an approach which the LUNG SAFE study [2] has clearly shown is insufficiently used. It is only after limiting plateau pressure sufficiently that we can envisage limiting driving pressure in cases when severely altered lung compliance mandates use of insuf- ficient 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 – The 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. EXPERT OPINION Rationale: PEEP is an integral part of the protective ventilation strategy. The expected beneficial effect 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 effects of high PEEP are increased end-inspiratory lung volume, hence increased risk of volutrauma [13], 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 effects of intrinsic PEEP are, during ARDS, identical to those of external PEEP [42, 43]. The extent of the beneficial and deleterious effects of high PEEP varies greatly from one patient to another and Page 7 of 18Papazian et al. Ann. Intensive Care (2019) 9:69 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 [46]. Individually, the effect 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 quantification 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 [24]. Thus, 12  cmH2O can be consid- ered as the threshold above which PEEP can be qualified as high. No significant difference 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 …