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Contents lists available at ScienceDirect

Journal of Intensive Medicine

journal homepage: www.elsevier.com/locate/jointm

Ten golden rules for individualized mechanical ventilation in acute

respiratory distress syndrome
Denise Battaglini a,b,1, Marco Sottano a,c,1, Lorenzo Ball a,c, Chiara Robba a,c, Patricia R.M. Rocco d,
Paolo Pelosi a,c,∗
a
Anesthesia and Intensive Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neuroscience, Genoa 16132, Italy
b
Department of Medicine, University of Barcelona, Barcelona 08007, Spain
c
Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa 16126, Italy
d
Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil

a r t i c l e i n f o a b s t r a c t

Keywords: Considerable progress has been made over the last decades in the management of acute respiratory distress
Acute respiratory distress syndrome (ARDS) syndrome (ARDS). Mechanical ventilation(MV) remains the cornerstone of supportive therapy for ARDS. Lung-
Protective mechanical ventilation protective MV minimizes the risk of ventilator-induced lung injury (VILI) and improves survival. Several parame-
Extracorporeal CO2 removal (ECCO2 R)
ters contribute to the risk of VILI and require careful setting including tidal volume (VT ), plateau pressure (Pplat ),
Extracorporeal membrane oxygenation
driving pressure (ΔP), positive end-expiratory pressure (PEEP), and respiratory rate. Measurement of energy
(ECMO)
and mechanical power allows quantification of the relatives contribution of various parameters (VT , Pplat , ΔP,
PEEP, respiratory rate, and airflow) for the individualization of MV settings. The use of neuromuscular blocking
agents mainly in cases of severe ARDS can improve oxygenation and reduce asynchrony, although they are not
known to confer a survival benefit. Rescue respiratory therapies such as prone positioning, inhaled nitric oxide,
and extracorporeal support techniques may be adopted in specific situations. Furthermore, respiratory weaning
protocols should aloso be considered. Based on a review of recent clinical trials, we present 10 golden rules for
individualized MV in ARDS management.

Introduction tory strategies to mitigate VILI risk in critically ill patients with ARDS
[6]. Several randomized controlled trials (RCTs) and observational stud-
Acute respiratory distress syndrome (ARDS) was first described more ies have investigated the role of lung-protective MV on ARDS out-
than 50 years ago [1]. Despite substantial research on causal/supportive come, thus revolutionizing conventional ventilatory management [7–
therapies since then, ARDS remains hard to treat,with 33.2 deaths in 11]. Moreover, extracorporeal carbon dioxide removal (ECCO2 R) [12],
every 100,000 ARDS-related cases in the United States and between 2.6 extracorporeal membrane oxygenation (ECMO) [13], inhaled vasodila-
and 7.2 in every 100,000 people in Europe, with a declining annual rate tors [14], neuromuscular blocking agents (NMBAs) [15], and prone po-
[2]. sitioning [16–17] have been discussed by multidisciplinary groups in
It is estimated that more than 3 million people/year are affected recent guidelines as potential rescue strategies for more severe cases
by ARDS [3]. ARDS Accounting for up to 10% of intensive care unit [18–19].
(ICU) admissions each year globally and requiring mechanical ventila- The aim of this review is to provide health practitioners with an up-
tion (MV) that can itself damage the already injured ARDS lung [4]. to-date list of golden rules for diagnosing, classifying, and treating ARDS
Ventilator-induced lung injury (VILI) is the main consequence of inju- according to new findings in this research area.
rious MV [5]. Great effort has been made to identify possible ventila-

∗
Corresponding author at: Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa 16132, Italy.
E-mail address: [email protected] (P. Pelosi).
1
Denise Battaglini and Marco Sottano contributed equally.

https://doi.org/10.1016/j.jointm.2021.01.003
Received 21 December 2020; Received in revised form 21 January 2021; Accepted 23 January 2021
Available online xxx
2667-100X/© 2021 The Authors. Published by Elsevier B.V. on behalf of Chinese Medical Association. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
Please cite this article as: D. Battaglini, M. Sottano, L. Ball et al., Ten golden rules to individualize mechanical ventilation in acute respiratory
distress syndrome, Journal of Intensive Medicine, https://doi.org/10.1016/j.jointm.2021.01.003
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Rule 1. Classification of severity A recent study comparing VT ≤ 6.5 ml/kg and ≥6.5 ml/kg found that an
increase of 1 ml/kg PBW was associated with an increased risk of death
ARDS is a syndrome and not a disease [20], that is characterized by (hazard ratio=1.23, 95% confidence interval [CI]: 1.06–1.44, P=0.008)
inflammatory lung injury resulting in parenchymal stiffening and con- [28]. In contrast, in the LUNG SAFE study, VT ≥ 7.1 ml/kg was not asso-
solidation, alveolar closure, altered vascular permeability, an increase ciated with increased mortality but Pplat , PEEP, and ΔP were shown to
in lung water content and, eventually, severe gas exchange failure with significantly influence outcome measures [29]. Thus, Pplat is an impor-
acute onset of hypoxemia. The most current definition of ARDS is the tant parameter in the pathogenesis of VILI along with VT and PEEP, all of
Berlin definition, proposed in 2012 by a consensus panel of experts [21], which are included in the calculation of static compliance [30]. A lower
which ontlines the following 4 criteria that must be simultaneously met VT was associated with better survival but only if Pplat was <27 cmH2 O
for a diagnosis of ARDS: (1) a certain degree of hypoxemia, evaluated [31]; on the other hand, a high VT was associated with increased oxy-
by measuring the partial pressure of oxygen (PaO2 )/fraction of inspired genation and improved compliance but also a higher rate of mortality
oxygen (FiO2 ) ratio; (2) acute onset of hypoxemia, with respiratory [31–32]. A recent study reported that Pplat was a more important deter-
symptoms beginning within 1 week of clinical insult; (3) presence of bi- minant of mortality and outcome than ΔP[33]. ΔP is defined as VT /Crs
lateral opacities on chest imaging that are not fully explained by pleural (respiratory system compliance). In this formula, VT is normalized to
effusion, alveolar/lobar collapse, or nodules; and (4) absence of cardiac Crs of the damaged respiratory system and may be a better predictor
failure and/or fluid overload. The Berlin definition also classifies ARDS of survival than VT scaled to normal lung volume using PBW, which
severity based on the PaO2 /FiO2 ratio with a positive end-expiratory is determined by height and sex [34]. In other words, ΔP represents
pressure (PEEP) or continuous positive airway pressure >5 cmH2 O: mild the distending volume in the respiratory system when VT is delivered
ARDS (PaO2 /FiO2 ratio between 200 and 300), with a predicted mor- by the ventilator. VT , PEEP, and Pplat may contribute to VILI but can
tality of 27%; moderate ARDS (PaO2 /FiO2 ratio between 100 and 200), also interact in a complex manner; therefore, the relationship between
with a predicted mortality of 32%; and severe ARDS (PaO2 /FiO2 ratio any single parameter and mortality is unclear [35]. As Crs is directly
<100), with a predicted mortality of 45% [21]. In 2013, Villar et al. associated with normal aerated lung volume, it was suggested the ΔP
[22] modified the definition of ARDS severity with the aim of assessing is the best parameter for predicting mortality in ARDS patients [36]. A
ICU mortality risk according to the PaO2 /FiO2 ratio; the authors tested posthoc analysis of published trials demonstrated that ΔP was highly
2 levels of PEEP and FiO2 (PEEP ≥5 and ≥10 cmH2 O and FiO2 ≥0.5 and correlated with mortality rate [34]. PEEP and VT may have protective
1.0) at 24 h after ARDS diagnosis, and concluded that ARDS risk strat- effects only in association with a decreasd ΔP. Another study suggested
ification is best achieved with PEEP ≥10 cmH2 O and FiO2 ≥0.5, with targeting ΔP to below 13–15 cmH2 O [37]. Whether PEEP should be set
a mortality rate of 17%, 41%, and 58% in mild, moderate, and severe to minimize the value of ΔP is debated; this increased mortality rate in
ARDS groups, respectively. As with ARDS risk stratification, ARDS phe- a recent trial [38]. Thus, setting parameters based on a reduction in ΔP
notypes have yet to be clearly defined. Calfee et al. [23] incorporated 2 is not recommended, and Pplat remains the most important parameter
phenotypes into their definition of ARDS. Phenotype 1 is characterized for protecting against lung damage [33]. Finally, the best ΔP should not
by less severe inflammation and shock. Phenotype 2 is characterized be used to optimize MV in ARDS.
by higher plasma concentrations of inflammatory biomarkers, lower
serum bicarbonate concentrations, more frequent use of vasopressors,
and higher prevalence of sepsis; it is also associated with a higher mor- Rule 3. PEEP
tality, fewer ventilator-free days, and different responses (eg, mortality
and ventilator-free days) to high PEEP vs. low PEEP, which is similar to PEEP is an essential aspect of ARDS management [21]. Benefits of
the phenotype of coronavirus disease 2019(COVID-19) [24]. Thus, the using PEEP include alveolar recruitment, reduction of intrapulmonary
Berlin definition and the classification of ARDS severity and prognostic shunt, and arterial oxygenation [39]; on the other hand, detrimental
accuracy remain controversial. effects include an increased end-inspiratory lung volume and elevated
risks of volutrauma and VILI [40]. Current guidelines recommend re-
serving high PEEP for patients with moderate or severe ARDS and avoid-
Rule 2. Tidal volume(VT ), plateau pressure(Pplat ), and driving ing it in mild cases [41]. In a secondary analysis of the Lung Open
pressure(𝚫P) Ventilation Study, patients with ARDS who showed improved oxygena-
tion with high PEEP had a lower risk of death (odds ratio=0.8; 95%
The previous convention for MV in ARDS was a tidal volume (VT ) of CI: 0.72–0.89), while changes in compliance and dead space were un-
10–15 ml/kg of predicted body weight (PBW) [8].Over the past decades, related to mortality [42]. The threshold for defining high vs. low PEEP
much has been learned concerning the detrimental sequelae of MV such is 12 cmH2 O [19]. A recent meta-analysis comparing low VT combined
as lung overdistention (eg, in the case of a high VT ) with subsequent vo- with high or low PEEP found that a high PEEP improved survival (rela-
lutrauma, which along with atelectrauma and biotrauma constitutethe tive risk=0.58; 95% CI: 0.41–0.82; P=0.05) [43]. Three large RCTs com-
basis for VILI [25–26]. A multicenter conducted in 2000 changed the paring high and moderate PEEP levels in ARDS patients ventilated with
clinical management of ARDS. The trial was interrupted after enrolling low VT (6 ml/kg PBW) did not find any differences in mortality [44–46].
861 patients because of a higher mortality rate and fewer ventilator- High PEEP was associated with lower mortality in patients with mod-
free days in patients treated with conventional VT (12 ml/kg of PBW erate and severe ARDS and higher mortality in those with mild ARDS
and Pplat of 50 cmH2 O) compared to those treated with a lower VT [47]. A high PEEP level is associated with increased static stress, but is
(6 ml/kg of PBW and Pplat of 30 cmH2 O) [8]. The ARDSNet study at- required to avoid repeated opening and closing of alveolar units [48].
tempted to maintain the partial pressure of carbon dioxide (PaCO2 ) as The ART trial demonstrated that a PEEP value >15 cmH2 O was associ-
close to the normal range as possible, resulting in a higher respiratory ated with increased mortality, especially in patients with hemodynamic
rate (25–30 breaths/min), which is often required to maintain PaCO2 be- impairment and pneumonia [38]. Therefore, we do not recommend us-
low 50 mmHg but can lead to dynamic hyperinflation and insufflation. ing an average PEEP level >15 as this could compromise hemodynamic
Although hypercapnia can induce catecholamine release and increase function and increase the need for fluids.
pulmonary vascular resistance, it also suppresses inflammation and the There are no definitive recommendations on how to set PEEP. In
production of free radicals [27]. Current guidelines suggest the use of a patients with moderate or severe ARDS, setting PEEP according to
heated humidifier to control hypercapnia; however, VT can be increased either transpulmonary pressure (PL ) or PEEP/FiO2 did not influence
over 6 ml/kg (PBW) in the case of marked and persistent hypercapnia mortality [38]. The best way to individualize PEEP is to use a low
with an already increased respiratory rate and reduced dead space [19]. PEEP/PaO2 /FiO2 table [49], as patients who require more PEEP have

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more recruitable lungs and vice versa. On the other hand, the use of the A recent meta-analysis of 6 RCTs involving 1423 ARDS patients
best ΔP or stress index, as well as PL at end expiration was associated showed a reduction in mortality with the use of RMs. Notably, 5 of
with higher PEEP in less recruitable lungs and lower PEEP in more re- the studies used a high PEEP in the intervention group, suggesting that
cruitable lungs. PEEP should be individualized, but without using ΔP RMs can be used in combination with an open lung-protection strategy.
and compliance as titration methods, giving that compliance decreases In the study that did not adopt the cointervention and used only pe-
with lung volume and recruitment (and is influenced by VT ); that is, riodic RMs without higher PEEP, mortality was reducted although the
the higher the compliance, the lower the ΔP. Higher PEEP increases quality of evidence was low. All 6 studies showed improved oxygena-
intra-tidal recruitment, which in turn increases compliance (although tion after 24 h (mean increase=52 mmHg; 95% CI: 23–81 mmHg). In
this is undesirable). Changes in ΔP from airway pressure may be partly another meta-analysis of 10 trials using high PEEP only (n = 3), RMs
explained by changes in chest wall compliance in patients with high only (n = 1), or their combination (n = 6), there was no differences in
abdominal pressure. The following thresholds should be respected to mortality rate (RR=0.96, 95% CI: 0.84–1.09, P = 0.5), or incidence of
minimize the risk of VILI: Pplat should be maintained as low as possible barotrauma (RR=1.22, 95% CI: 0.93–1.61, P = 0.16) [7]. Regarding the
(<25–27 cmH2 O); and ΔP should be low to reduce mechanical power detrimental effects associated with RMs, there was no increase in the
(MP) in association with a reduction of VT , although a lower ΔP does risk of barotrauma (4 trials; RR = 0.84; 95% CI: 0.46–1.55) or incidence
not reduce MP in association with the optimal PEEP (set as ΔP). Fi- of hemodynamic compromise (3 trials; RR=1.30; 95% CI: 0.92–1.78)
nally, the outdated concept of high vs. low PEEP should be abandoned. [64]. Various lung RMs have been used including high airway pressure
In an experimental model, a higher PEEP increased static strain and sustained for a limited amount of time, a stepwise increase in PEEP with
VILI, while volutrauma caused more lung damage than atelectrauma fixed ΔP, etc [65–68]; this heterogeneity may limit the accuracy of meta-
[50–51]. analyses.
PEEP should be set at the lowest level that is needed to attain Further studies are needed to evaluate the beneficial effects of RMs;
minimal acceptable oxygen saturation (SpO2 ) (88–92%) or PaO2 (55– at present, they are not recommended in treatment guidelines for pa-
70 mmHg) [52]. PaO2 and oxygen delivery can be optimized by in- tients with severe ARDS [19].
creasing blood pHa and reducing PaCO2 , which increases hemoglobin
concentration, cardiac output, and arterial oxygen content. Clinicians
should exercise caution when adopting lung-protective strategies, par- Rule 5. Neuromuscular blocking agents(NMBA4)
ticularly with low oxygen targets and permissive hypercapnia [53].
PEEP should also be set to protect the right ventricle, because the re- NMBAs act by inhibiting patients’ active breathing. Patients with
cruitment of lung units leads to derecruitment of capillaries. At high severe ARDS may benefit from NMBAs, especially those with higher
PEEP, more fluids are needed to achieve capillary recruitment and im- APACHE-II score, alveolar-arterial oxygen gradients, and Pplat , who re-
prove right ventricle function and lymphatic flow drainage from the quire rescue therapies such as prone position and ECMO [17–69]. NM-
lungs is reduced [54]. BAs reduce patient-ventilator asynchronies and oxygen consumption
Personalized ventilatory treatment optimized based on chest X- and increase compliance, functional residual capacity, and regional dis-
rays and computed tomography (CT) scans did not yield better out- tribution of VT , resulting in anti-inflammatory effects [15–70]. NMBAs
comes and was even associated with a worse outcome [55], suggesting also play a critical role in limiting decruitment and maintaining PEEP,
that chest imaging is not the best approach to optimize MV in ARDS thereby reducing fluctuations in PL caused by strong inspiratory effort
patients. and expiratory alveolar collapse [71]. A major side effect of long term
Obese patients are at a particularly high risk of developing ARDS be- NMBA administration is muscular weakness, which can be a detrimental
cause of anatomic and physiologic alterations affecting the chest wall, during in weaning from MV.
lungs, pharynx, face, and neck [56]. These patients present with reduced A recent meta-analysis evaluating the effects of NMBAs on the out-
functional residual capacity and lung compliance, hypoxia, and ventila- come of ARDS patients found that NMBAs did not reduce mortality
tion/perfusion mismatch. Applying PEEP in this population is important risk at 28 days (RR = 0.9; 95% CI: 0.78–1.03; P=0.12) and 90 days
to mitigate atelectasis and distal airway closure. In this regard, airway (RR = 0.81; 95% CI: 0.62–1.06; P=0.06), but significantly reduced ICU
occlusion at end-inspiration is a useful method for individualizing PEEP mortality risk (RR = 0.72; 95% CI: 0.57–0.91; P=0.007), ventilator-free-
according to a patient’s specific physiology [57–59]. days, and duration of MV,and increased oxygenation (eg, by decreasing
We do not recommend using a PEEP level >15 cmH2 O. Low VT com- the incidence of asynchronies) [72]. This meta-analysis did not include
bined with the minimum PEEP level needed to achieve saturation/PaO2 the ROSE trial [72], because the authors used a modified PEEP table
targets (88%–92%/55–70 mmHg) [52] is the best option to avoid re- and not the National Heart, Lung, and Blood Institute protocol used
peated collapse and reopening of alveoli, essentially by closing down in the other RCTs; moreover, the patients were only lightly sedated,
the lungs and keeping them at rest to minimize VILI [60]. The distinc- in contrast to the deep-sedation strategy used in the other trials. This
tion between high and low PEEP should be abolished and PEEP should could explain why in the ROSE trial, ARDS patients had a lower rate of
be individualized based on the functional characteristics of each ARDS vasopressor use, shorter intubation time, and lower mortality rate. In
patient. the ROSE trial, patients with moderate-to-severe ARDS were randomly
divided into 2 groups(heavy sedation with NMBAs and light sedation
Rule 4. Recruitment maneuvers(RMs) with placebo instead of NMBAs); the same high PEEP ventilation and
fluid conservation strategies were used in both groups to avoid the con-
The total weight of the lungs is increased in ARDS due to interstitial founds of co-intervention. There were no differences in mortality rate
and alveolar edema. As a result, atelectasis in dependent areas of the at 28 and 90 days, and the incidence of muscle weakness was similar
lungs is common; the collapse of alveoli not only reduces the total lung between groups [73]. In the ACURASYS trial, mortality at 90 days did
surface available for gas exchange but also promotes lung injury by in- not differ between the NMBA (31.6%; 95% CI: 25.2–38.8) and placebo
creasing shear stress in areas located at the interface between aerated (40.7%; 95% CI: 33.5–48.4) group (P=0.08), although mortality at 28
and collapsed alveoli, which undergo cyclic recruitment and derecruit- days differed slightly at 23.7% (95% CI: 18.1–30.5) and 33.3% (95%
ment [61]. RMs decrease the intrapulmonary shunt and improve oxy- CI: 26.5–40.9) in the NMBA and placebo groups, respectively (P=0.05)
genation and compliance. Thus, RMs can be considered as a protective [10].
“open lung approach” to MV; although it can lead to hemodynamic im- In summary, NMBAs do not reduce mortality risk at 28 and 90 days,
pairment and overdistension, which is more harmful than atelectrauma ventilator-free days, or duration of MV, but improve oxygenation and
[62–63]. reduce barotrauma without affecting ICU weakness. Fig. 1 outlines a

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Fig. 1. Proposed algorithm for NMBAs use in ARDS patients. NMBA use is suggested when moderate to severe ARDS is present. NMBAs plays a pivotal role in
limiting decruitment and maintaining PEEP, allowing a reduction in swings of transpulmonary pressure due to strong inspiratory effort and expiratory alveolar
collapse. ARDS: Acute respiratory distress syndrome; BGA: Blood gas analysis; BIS: Bispectral index; ICU: Intensive care unit; NMBA: Neuromuscular blocking agent;
PBW: Predicted body weight; PEEP: Positive end-expiratory pressure; RASS: Richmond Agitation Sedation Scale.

management algorithm for the use of NMBAs in patients with moderate- of gravity, dependent areas are also more extensively perfused, resulting
to-severe ARDS. in hypoxemia due to ventilation/perfusion mismatch. Marked increases
in oxygenation are frequently observed in ARDS patients in the prone
Rule 6. Assisted ventilation position as a more homogeneous ventilation/perfusion ratio is achieved
and intrapulmonary shunt is consequently diminished [78]. The prone
In the acute phase of ARDS, it is reasonable to maintain the patients position not only improves oxygenation but also reduces the risk of VILI
on continuous NMBA treatment in a protective, controlled ventilation [79]. Improved oxygenation with no change in PaCO2 leads to the re-
mode. When there is clinical improvement, withdrawal from MV should distribution of perfusion instead of recruitment because regional ven-
be initiated. Spontaneous breathing has favorable effects such as reduc- tilation does not improve. On the other hand, improved oxygenation
ing the wasting of respiratory muscles and improving oxygenation and associated with reducted PaCO2 leads to recruitment and increases re-
compliance [74]. NMBAs and sedatives are first withdrawn until a spon- gional ventilation and survival [80].
taneous breathing effort is observed. Return to spontaneous ventilation Conflicting findings have been reported regarding the benefits of the
is as inevitable as it is challenging. There are several problems associated prone position. The Prone-supine-II RCT [81], which enrolled 342 adult
with so-called pressure-support ventilation (PSV) modes. Spontaneous ARDS patients with moderate and severe hypoxemia, found no signif-
breathing can increase the inflammatory response and VILI [75] and an icant differences in overall survival at 28 days and 6 months between
intense breathing effort due to exaggerated respiratory drive can worsen supine and prone patients (for 20 h/day); however, complications were
patient self-inflicted lung injury caused by the hyperinflation of aerated significantly higher in the latter group. A recent meta-analysis of 8 RCTs
lung areas with increased strain. As a general rule, criteria for protection also showed no difference in mortality between groups but in a sub-
similar to those applied to controlled ventilation in ARDS [36] must be group analysis, mortality was lower in patients who were pronated for
met for assisted spontaneous ventilation. With regard to the ventilator ≥ 12 h/day;moreover, PaO2 /FiO2 ratio was higher and complications
mode before weaning and extubation, a recent non-inferiority RCT com- such as pressure sores and endotracheal tube obstruction were more fre-
paring assisted ventilation without or with the sigh maneuver in acute quent in the prone position group [82]. In the PROSEVA trial involving
hypoxemic patients showed that 23% of patients in the latter group 466 patients with severe ARDS, the intervention group (237 patients)
failed to remain on pressure-control ventilation, compared to 30% in remained in the prone position for 16 h/day (an average of 4 sessions
the assisted ventilation only group (absolute difference, −7%; 95% CI: of prone positioning per patient); mortality was significantly lower in
−18% – 4%; P=0.015), highlighting the clinical benefit of using the sigh these patients at 28 days and at 90 days while the rate of complications
maneuver during assisted ventilation [76]. was comparable to that in the supin groups, except for cardiac arrest
, which occurred more frequently in the latter [83]. These data sug-
Rule 7. Prone positioning gest that prone positioning may have clinical benefits in severe cases of
ARDS, provided that it is maintained for at least 16 h.
The ventilation of dependent areas is severely impaired in the supine Current guidelines recommend cycles of prone positioning lasting at
position in ARS patients compared to non-ARDS patients [77]. Because least 16 h for patients with PaO2 /FiO2 <150 in order to reduce mor-

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tality. Pronation is cost effective and relatively easy to implement, al- the list for lung transplantation; or cardiac or respiratory collapse [90–
though the correct and safe positioning of patients requires technical 92]. ECMO should also be used to reduce the risk of VILI by adopting an
skills and extreme caution [18]. Prone positioning for 1 day (12–18 h) ultra-protective ventilator strategy [93]. While absolute contraindica-
repeated 3 times (2–5 days) is a reasonable schedule. tions are not available, relative contraindications should be considered
Prone positioning is the best technique for opening up the lungs and such as >7 days of maximal MV settings; immunosuppression; central
keeping them open, but at minimal acceptable oxygenation and airway nervous system hemorrhage, damage or terminal malignancy; and in-
pressure and lower PEEP. In this context, PEEP should be set to minimize creased age [88].
injurious static strain. A strategy for selecting patients who may benefit from rescue strate-
gies is presented in Fig. 2.
Rule 8. Other rescue therapies
Rule 10. Weaning from mechanical ventilation
Rescue therapies for ARDS are indicated when other less inva-
sive strategies are unsuccessful. ECCO2 R with a blood flow up to
Once lower desirable levels of pressure support under assisted venti-
1.500 ml/min is an effective therapy for ARDS patients with either hy-
lation have been achieved, sedatives and analgesics should be reduced
poxemic or hypercapnic respiratory failure. Artificial lungs are commer-
and a spontaneous breathing trial (SBT) conducted. Post-extubation res-
cially available, that may be used within a conventional system of cen-
piratory failure is associated with a high risk of mortality [94–96]. Daily
trifugal pumps separate from or within a continuous renal replacement
interruption of sedation to assess the levels of agitation and pain has
therapy circuit [84]. In our opinion, the circuits and pumps should be
been adopted since 2000; this practice can reduce days on MV and
further improved in the near future. This system is attractive because it
length of ICU stay [97]. Weaning from MV can be categorized as simple,
allows low-flow CO2 removal in severe cases of ARDS, while avoiding
difficult, and prolonged [98]. Several methods have been proposed to
the invasiveness of high-flow ECMO. Low-flow CO2 removal maintains
predict successful weaning from MV, each with advantages and limita-
oxygenationwith less MP, and can be easily and safely applied at the
tions; the most commonly used metric is the frequency/VT ratio [99].
bedside [84–85]. ECCO2 R protects against VILIg by reducing VT and
Weaning strategies that are often used in general ICU patients in-
Pplat while also controlling respiratory acidosis [86]; however, questions
clude PSV or a T-tube trial. In an RCT comparing 30 min of low PSV (8
remain regarding its indications as most of the data come from observa-
cmH2 O and 0 PEEP) and 2 h with a T-tube, the former yielded greater
tional studies of small case series or from retrospective analyses. A con-
success with extubation. However, although the decision to connect the
sensus statement published in 2020 on ECCO2 R use in ARDS patients
patient to a high-flow nasal cannula or administer non-invasive ven-
defined the target criteria for MV as follows: ΔP < 14 cmH2 O, Pplat <
tilation (NIV) after extubation, or to reconnect the patient 1 h before
25 cmH2 O, and a respiratory rate of 20–25 breaths/min. Indications for
extubation was made during the randomization phase, the PSV arm re-
starting ECCO2 R include ΔP > 15–20 cmH2 O, Pplat > 30–35 cmH2 O,
ceived high-flow nasal cannulation or NIV for a longer period than the
PaCO2 ≥ 60 mmHg, pH < 7.25, respiratory rate > 20–30 breaths/min,
T-tube arm (25% vs. 19%; P=0.01), potentially confounding the final
PaO2 /FiO2 < 150, and PEEP > 8–15 cmH2 O [86].
results [100]. Moreover, in some trials, patients were reconnected to
Inhaled nitric oxide (iNO) is another rescue strategy often used in
the ventilator for a certain interval before extubation, whereas in others
ARDS patients who do not respond to conventional treatments. iNO was
they were directly extubated after passing an SBT. Another RCT con-
first reported in 1987 as an endogenous vasodilator to treat pulmonary
ducted in 2017 demonstrated that a 1-h rest period after passing an SBT
hypertension and other pulmonary diseases; it was recently, shown to
reduced the rate of reintubation within 48 h after extubation [101]. A
be advantageous for ventilation/perfusion mismatch. Current data indi-
practical guideline for weaning is performing the SBT with inspiratory
cate that iNO can be safely applied, although potential adverse effects
pressure augmentation and a PEEP level between 0 and 5 cmH2 O fol-
include methemoglobinemia, reduced platelet aggregation, systemic va-
lowed by extubation and NIV in patients at high risk of extubation failure
sodilation, and renal dysfunction. Thus, iNO should be used carefully in
(eg, patients with hypercapnia, chronic obstructive pulmonary disease,
patients with renal diseases, and renal function should be strictly mon-
congestive heart failure, or other serious comorbidities) [102]. Person-
itored during the treatment [87].
alized approaches for weaning general ICU patients need to be safer
and faster. As specific studies on weaning in ARDS are not yet available,
Rule 9. ECMO
we recommend following local protocols based on current evidence ob-
tained from the general ICU population. Additionally, the role of respira-
While low-flow systems such as ECCO2 R (0.5–1.5 L/min) provide ad-
tory physiotherapy is critical in this setting. Chest physiotherapy should
equate flow for both oxygenation and CO2 removal, high-flow systems
be initiated as soon as possible even during controlled MV to improve
such as ECMO (2–4 L/min) provide too much flow for minimal oxygena-
outcome and reduce complications. In particular, assisted mobilization,
tion and CO2 removal (for which a low blood flow is needed) [86–88]. In
postural therapy, neuromuscular electrical stimulation, and respiratory
the EOLIA trial, ECMO was used in patients who were already pronated
muscle training can reduce muscle weakness in ICU patients, and while
but did not show sufficient improvement. The trial failed to demonstrate
manual or ventilator hyperinflation [103], positioning [104], an active
a significant difference in 60-day mortality between ECMO and control
breathing cycle, and subglottic secretion drainage canreduce respiratory
groups [69]. A recent meta-analysis of 2 RCTs with a total of 429 pa-
complications such as atelectasis, ventilator-associated pneumonia, and
tients reported a lower 60-day mortality in the venous-venous ECMO
tracheobronchitis [105].
group (RR=0.73; 95% CI: 0.58–0.92; P=0.008), whereas 3 other studies
reported a higher incidence of major hemorrhage in patients receiving
ECMO [89]. Not all centers participating in these trials adopted the con- COVID-19 ARDS
ventional rescue strategies for severe ARDS cases, and some lackedex-
pertise in the use of ECMO. The latest Extracorporeal Life Support Orga- Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was
nization guidelines for initiating ECMO include hypoxic respiratory fail- first identified in Wuhan, China in late 2019. It subsequently spread
ure with a mortality risk≥50% or greater (PaO2 /FiO2 < 150 with FiO2 > worldwide and rapidly became a pandemic. Most cases of infection with
90% and/or Murray score of 2–3, Age-Adjusted Oxygenation Index(AOI) the virus are limited to mild febrile illness, but some develop ARDS
score of 60, or APSS score of [based on age, PaO2 /FiO2 , and the Pplat ]), a that requires ICU admission and critical care [106–107]. The respira-
risk of mortality ≥80% (PaO2 /FiO2 < 100 with FiO2 > 90%, and/or Mur- tory management of COVID-19 ARDS is based on distinct phenotypes
ray score 3–4, AOI score >80, or APSS score of 8); retention of PaCO2 according to chest CT findings [24,108–110] and lung physiology; these
despite maximal settings for MV; severe air leak syndrome; patients on include phenotype 1, with preserved lung compliance but few alveolar

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D. Battaglini, M. Sottano, L. Ball et al. Journal of Intensive Medicine xxx (xxxx) xxx

Fig. 2. Proposed algorithm for rescue strategies. ECCO2 R: Extracorporeal CO2 removal; FiO2 : Fraction of inspired oxygen; iNO: Inhaled nitric oxide; PaCO2 : Partial
pressure of carbon dioxide; PaO2 : Partial pressure of oxygen; VV-ECMO: Venous-venous extracorporeal membrane oxygenation.

Fig. 3. Simplified formulas for mechanical power (MP) for volume-controlled and pressure-controlled ventilation. A: Mechanical power formula for volume-control
ventilation. B: Mechanical power formula for pressure-controlled ventilation. Elastic static, dynamic, and resistive forces in yellow, blue, and green, respectively.
MP: Mechanical power; PCV: Pressure-controlled ventilation; PEEP: Positive end-expiratory pressure; P peak: Peak pressure; Pplat : Plateau pressure; RR: Respiratory
rate; VCV: Volume-controlled ventilation; VT : Tidal volume.

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areas to recruit, along with high-perfusion areas; phenotype 2, with non- [3] Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. Inci-
homogeneously distributed atelectasis; and phenotype 3, featuring low dence and outcomes of acute lung injury. N Engl J Med 2005;353(16):1685–93.
doi:10.1056/NEJMoa050333.
compliance and inhomogeneous distribution of atelectasis(very similar [4] Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiol-
to traditional ARDS) [108]. ogy, patterns of care, and mortality for patients with acute respiratory distress
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doi:10.1001/jama.2016.0291.
ARDS patients, for phenotype 1 COVID-19 ARDS, we suggest using mod- [5] Silva PL, Ball L, Rocco PRM, Pelosi P. Power to mechanical power to mini-
erate PEEP to redistribute pulmonary blood flow from non-ventilated to mize ventilator-induced lung injury? Intensive Care Med Exp 2019;7(Suppl 1):38.
more ventilated areas. For phenotype 2, we recommend using moderate- doi:10.1186/s40635-019-0243-4.
[6] Battaglini D, Robba C, Rocco P, De Abreu MG, Pelosi P, Ball L. Perioperative
to-high PEEP to improve lung recruitment; rescue therapies can also be
anaesthetic management of patients with or at risk of acute distress respira-
considered. For phenotype 3, we suggest adopting the current recom- tory syndrome undergoing emergency surgery. BMC Anesthesiol 2019;19(1):153.
mendations for typical (non-COVID) ARDS [24,105–111]. doi:10.1186/s12871-019-0804-9.
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Recent studies have demonstrated that not only static parameters [8] Network Acute Respiratory Distress Syndrome, RG Brower, Matthay MA, Mor-
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[10] Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al. Neu-
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levels >27 J/min should be considered during ECMO [119]. The con-
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tilation to minimize the risk of VILI. When it is impossible to optimize [17] Guérin C, Mancebo J. Prone positioning and neuromuscular blocking agents
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Funding
[21] Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E,
et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA
This work was funded by the Brazilian Council for Scientific and 2012;307(23):2526–33. doi:10.1001/jama.2012.5669.
Technological Development (COVID-19-CNPq), Rio de Janeiro State Re- [22] Villar J, Pérez-Méndez L, Blanco J, Añón JM, Blanch L, Belda J, et al. A universal
definition of ARDS: the PaO2/FiO2 ratio under a standard ventilatory setting–a
search Foundation (COVID-19- FAPERJ), Funding Authority for Studies prospective, multicenter validation study. Intensive Care Med 2013;39(4):583–92.
and Projects (FINEP), and Brazilian Ministry of Science, Technology, doi:10.1007/s00134-012-2803-x.
and Information COVID-19 Network (RedeVírus MCTI). [23] Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA. Sub-
phenotypes in acute respiratory distress syndrome: latent class analysis of data
from two randomised controlled trials. Lancet Respir Med 2014;2(8):611–20.
Declarations of Competing Interest doi:10.1016/S2213-2600(14)70097-9.
[24] Robba C, Battaglini D, Ball L, Patroniti N, Loconte M, Brunetti I, et al. Distinct
phenotypes require distinct respiratory management strategies in severe COVID-
All authors declare they have no conflicts of interest. 19. Respir Physiol Neurobiol 2020;279:103455. doi:10.1016/j.resp.2020.103455.
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