Management of Severe Acute Respiratory Distress Syndrome: A Primer PDF

Grotberg et al. Critical Care (2023) 27:289 Critical Care https://doi.org/10.1186/s13054-023-04572-w REVIEW...

Grotberg et al. Critical Care (2023) 27:289 Critical Care https://doi.org/10.1186/s13054-023-04572-w REVIEW Open Access Management of severe acute respiratory distress syndrome: a primer John C. Grotberg1*, Daniel Reynolds1 and Bryan D. Kraft1 Abstract This narrative review explores the physiology and evidence-based management of patients with severe acute respira- tory distress syndrome (ARDS) and refractory hypoxemia, with a focus on mechanical ventilation, adjunctive therapies, and veno-venous extracorporeal membrane oxygenation (V-V ECMO). Severe ARDS cases increased dramatically worldwide during the Covid-19 pandemic and carry a high mortality. The mainstay of treatment to improve survival and ventilator-free days is proning, conservative fluid management, and lung protective ventilation. Ventilator settings should be individualized when possible to improve patient-ventilator synchrony and reduce ventilator-induced lung injury (VILI). Positive end-expiratory pressure can be individualized by titrating to best respiratory system compli- ance, or by using advanced methods, such as electrical impedance tomography or esophageal manometry. Adjust- ments to mitigate high driving pressure and mechanical power, two possible drivers of VILI, may be further beneficial. In patients with refractory hypoxemia, salvage modes of ventilation such as high frequency oscillatory ventilation and airway pressure release ventilation are additional options that may be appropriate in select patients. Adjunctive therapies also may be applied judiciously, such as recruitment maneuvers, inhaled pulmonary vasodilators, neuro- muscular blockers, or glucocorticoids, and may improve oxygenation, but do not clearly reduce mortality. In select, refractory cases, the addition of V-V ECMO improves gas exchange and modestly improves survival by allowing for lung rest. In addition to VILI, patients with severe ARDS are at risk for complications including acute cor pulmonale, physical debility, and neurocognitive deficits. Even among the most severe cases, ARDS is a heterogeneous disease, and future studies are needed to identify ARDS subgroups to individualize therapies and advance care. Keywords Acute respiratory distress syndrome, Extracorporeal membrane oxygenation, Positive end expiratory pressure, Driving pressure, Mechanical power, Electrical impedance tomography, Esophageal manometry, Acute cor pulmonale Introduction [2, 3]. ARDS pathophysiology is rooted in the disrup- The acute respiratory distress syndrome (ARDS), first tion of the alveolar capillary barrier by inflammatory described in 1967 , is a common cause of respira- and oxidative insults. This results in the characteristic tory failure in the ICU. There are approximately 190,000 clinical (acute onset), radiographic (bilateral alveolar ARDS cases annually in the USA alone, although cases opacities), physiologic (reduced compliance, high shunt skyrocketed in 2020 due to the COVID-19 pandemic fraction), and histologic (classically diffuse alveolar dam- age) derangements. Severe ARDS, defined by an arterial partial pressure of oxygen (­PaO2) to fraction of inspired *Correspondence: oxygen ­(FiO2) ratio (P/F) ≤ 100, carries mortality close John C. Grotberg to 50%. In moderate-to-severe ARDS, positive end [email protected] 1 Division of Pulmonary and Critical Care Medicine, Washington University expiratory pressure (PEEP) may confound the P/F ratio, School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA and is addressed using the “P/FP ratio” ((PaO2*10)/ (FiO2*PEEP)), with P/FP ≤ 100 defining severe ARDS © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Grotberg et al. Critical Care (2023) 27:289 Page 2 of 15. The noninvasive ratio of pulse oximetric saturation Low tidal volume ventilation ­(SpO2) to ­FiO2, or the “S/F ratio”, also correlates well to Low tidal volume ventilation using either pressure-assist P/F ratios and is readily available at the bedside. Though control (PC) or volume-assist control (VC) modes signif- not clearly defined, S/F ratios of < 89 to < 120 approximate icantly improves mortality in ARDS [8, 11–13]. Neither severe ARDS [5–7]. mode is superior. A VC mode controls tidal volume Patients with severe ARDS are at high risk for ventila- at the expense of controlling airway pressures, whereas a tor-induced lung injury (VILI) and may develop refrac- PC mode controls airway pressures at the expense of tidal tory hypoxemia and hypercapnia. Traditional treatment volume and minute ventilation [15, 16]. Pressure regu- of severe ARDS is supportive, anchored by lung protec- lated volume control (PRVC) is an adaptive mode that tive mechanical ventilation, proning, and conservative adjusts tidal volume for set pressure limits but may be fluid management [8–10]. Adjunctive therapies (e.g., insufficient in patients with high ventilatory drives. inhaled pulmonary vasodilators, glucocorticoids) can The landmark ARMA trial demonstrated that a tidal be used, and in select cases, patients may require veno- volume of 6 cc/kg ideal body weight (IBW) compared venous extracorporeal membrane oxygenation (V-V to 12 cc/kg IBW reduced mortality (31% vs. 40%) and ECMO). This review will summarize the evidence-based increased ventilator-free days. While tidal volume management (Fig. 1) of severe ARDS emphasizing inter- ranged from 4 to 8 cc/kg in the trial, the goal tidal vol- ventions that improve outcomes. ume in the protocol was 4–6 cc/kg depending on plateau pressure (Pplat). Average tidal volume in the intervention Fig. 1 Severe ARDS Treatments. A schematic illustrating management strategies for severe ARDS and refractory hypoxemia. Green sections represent treatments that improve outcomes supported by prospective randomized controlled trials, the orange section represents a treatment that may improve outcomes based on retrospective data, the gray sections represent treatments that may improve oxygenation but have not demonstrated sustained clinical benefit in trials, and the purple sections represent treatments that likely derive benefit in a subset of patients. ARDS acute respiratory distress syndrome, IBW ideal body weight, Vt, tidal volume; and V-V ECMO, veno-venous extracorporeal membrane oxygenation. Adapted from “Risk Factors of Dementia,” by BioRender.com (2023). Retrieved from https://​app.​biore​nder.​com/​biore​nder-​templ​ates Grotberg et al. Critical Care (2023) 27:289 Page 3 of 15 arm was 6.2 cc/kg over the first 5 days of trial enrollment wave form. Increasing the flow or changing to a PC mode and 6.5 cc/kg was used as a cut-off to designate study-site can improve asynchrony. Conversely, excessive flow can adherence. Physiologically, lower tidal volume ventilation be improved by decreasing the flow in VC or decreasing reduces driving pressure, mechanical power, and the risk the inspiratory pressure in PC. of volutrauma on the ARDS lung [18–20]. However, low tidal volumes (4–6 cc/kg) may still result in barotrauma, Positive end expiratory pressure particularly in poorly compliant lungs. Barotrauma might PEEP opens collapsed alveoli allowing for recruited lung be mitigated by further reducing tidal volumes (to lower to participate in gas exchange and reduces alveolar over- airway pressures) in a VC mode, or with a PC mode. distension by increasing distribution of the tidal breath. While low tidal volume ventilation improves mortality There is no clear mortality benefit in ARDS when com- in ARDS, it may be poorly tolerated in some patients, paring high PEEP to low PEEP strategies in all patients leading to increased ventilator asynchrony and deeper receiving low tidal volume ventilation, however, there sedation. may be a benefit in patients with moderate-to-severe ARDS, particularly patients who are PEEP-responsive Ventilator asynchrony (defined as an increase in P/F > 25 mm Hg after higher Patient-triggered modes of mechanical ventilation reduce PEEP) [25–33]. Because of significant heterogeneity in work of breathing assuming matching between patient ARDS, different phenotypes may respond differently to respiratory efforts and ventilator-delivered breaths. PEEP , therefore, clinicians should monitor oxygena- Asynchrony events are common and may worsen out- tion and lung compliance during titration. PEEP titration comes if frequent. Asynchrony events can be quantified is performed by making stepwise increases in PEEP fol- by the asynchrony index (AI), defined as the number of lowed by small decremental changes of 2 cm H ­ 2O every asynchrony events divided by the sum of the number of 2–5 min while checking Pplat and monitoring changes in ventilatory cycles. In one study, 24% of the patients had lung compliance. If a patient’s oxygenation or lung com- an AI > 10%. Evidence suggests AI > 10% may be asso- pliance worsen with increased PEEP, the PEEP is too ciated with increased ICU and hospital mortality. high, whereas if they improve, the titration can continue Common asynchronies include triggering asynchrony, until no further improvement is observed. cycling asynchrony and flow asynchrony. Ineffective trig- More advanced methods for individualizing PEEP gering occurs when patient respiratory efforts do not include the stress index (SI), electrical impedance tomog- result in ventilator-delivered breaths and is improved by raphy (EIT), and esophageal pressure (Pes) guidance increasing the trigger sensitivity of the ventilator or by (Fig. 2). The SI is based on the pressure–time curve dur- using a flow-triggered. When ineffective triggering is due ing constant flow (square-wave) volume-control venti- to excess intrinsic PEEP, efforts are directed to reduce lation. A linear pressure rise suggests recruited alveoli intrinsic PEEP, or increase external PEEP to ~ 75% of the without overdistension (SI = 1). Increasing compliance intrinsic PEEP to decrease the pressure gradient required as the lungs are inflated (concave down waveform, SI < 1) by the patient to trigger the ventilator [23, 24]. Reverse suggests tidal recruitment, and benefit from increased triggering is seen in deeply sedated patients in which PEEP. Conversely, decreasing compliance as the lungs are mechanical insufflation triggers a muscular effort, gen- inflated (concave upward waveform, SI > 1) suggests over- erating a “patient-triggered” breath and can be resolved distension, and benefit from decreased PEEP (Fig. 2a) by decreasing the level of sedation or by adding a neu-. SI is not superior to other PEEP titration methods romuscular blocking agent. Cycling asynchronies [36, 37]. EIT determines the PEEP with the least overdis- occur cycling from the inspiratory to expiratory phase tended and collapsed lung (­PEEPODCL) (Fig. 2b) [38–41]. and may be premature or delayed. In premature cycling, In a study of severe ARDS, EIT-guided PEEP titration a patient’s respiratory effort continues during the expira- improved oxygenation, compliance and driving pressure tory phase resulting in double-triggering and breath. Finally, esophageal manometry can be used to guide stacking. This is addressed by increasing the inspiratory PEEP and operates under the assumption that the esoph- time in PC or by increasing the tidal volume or decreas- ageal pressure (Pes) is equivalent to the intrapleural pres- ing the flow in VC. The opposite occurs during delayed sure (Ppl). PEEP is titrated to a transpulmonary pressure cycling and is remedied by decreasing the inspiratory (PL) of 0 cm ­H2O, where PL = Pao − Pes, and Pao is the air- time in PC or increasing the flow in VC. Finally, flow way pressure. PPlat and PEEP can represent Pao as the asynchronies occur when patient flow demand does not alveolar distending pressure at end-inspiration or end- match that of the ventilator. Flow starvation more often expiration, respectively. In the EPVent trial, Pes-guided occurs in VC where patients exhibit excessive ventilatory PEEP titration improved oxygenation, however, when demand and typically “suck down” the pressure–time compared to empiric high PEEP in the EPVent-2 trial, Grotberg et al. Critical Care (2023) 27:289 Page 4 of 15 Fig. 2 Advanced methods of PEEP titration. A The stress index, based on the pressure–time curve during constant flow (square-wave) volume-control ventilation. B Electrical impedance tomography with a proposed decremental PEEP titration. The top image depicts global tidal impedance where white indicates the highest volume change, and the bottom image depicts areas of alveolar over-distension (orange) and collapse (white). C Esophageal manometry and associated transpulmonary pressure targets. P­ EEPODCL, PEEP with least over-distended and collapsed lung; PL, transpulmonary pressure; SI, stress index. Created with BioRender.com there was no difference in clinical outcomes [43, 44]. A was associated with greater survival than more positive post hoc analysis of the EPVent-2 trial demonstrated or more negative values. Ideal goals of esophageal that PEEP titrated to an end-expiratory PL of 0 cm ­H2O manometry to guide PEEP include (1) end-inspiratory Grotberg et al. Critical Care (2023) 27:289 Page 5 of 15 PL < 15–20 cm ­H2O, (2) end-expiratory PL = 0 cm H ­ 2O PEEP should be used (20–25 cm ­H2O). Sustained infla- (± 2 cm ­H2O), and (3) transpulmonary driving pres- tion should be avoided to reduce the risk of hemody- sure (end-inspiratory PL—end-expiratory PL) < 10–12 namic instability. cm ­H2O (Fig. 2c). A newer and elegant method of determining lung recruitability by PEEP is the recruit- Driving pressure ment-to-inflation ratio, where a ratio ≥ 0.5 suggests lung In contrast to adjusting tidal volume for IBW, driving recruitability at higher PEEP. pressure adjusts tidal volume for compliance, and is the Regardless of the method used for PEEP titration and change in tidal volume relative to the static compliance the metric(s) used assessing efficacy, monitoring hemo- of the respiratory system (Vt/CRS), or the pressure dif- dynamic responses is also necessary. PEEP can decrease ferential required to inflate the lungs (Pplat–PEEP). High cardiac output (by decreasing preload and increasing RV driving pressures (> 15–17 cm ­H2O) are independently afterload), which can decrease D ­ O2 despite an increase linked to ARDS mortality [58–62]. Amato et al. re-ana- in oxygen saturation. Conversely, PEEP can reduce LV lyzed data from 3562 patients from 9 trials and found afterload. Therefore, individualized PEEP titrations driving pressure was the variable that best stratified risk; should consider oxygenation and driving pressure as well reductions in driving pressure were strongly associated as hemodynamics. with increased survival. The association between driving pressure and mortality was also observed in the Recruitment maneuvers LUNG SAFE study. Newer analyses suggest that the A recruitment maneuver is a technique to increase the mortality benefit seen in lowering tidal volume varies airway pressure in the lungs temporarily. Common meth- with respiratory system compliance, with greater benefit ods used include sustained inflation (e.g. 35–40 cm H ­ 2O seen in patients with higher lung elastance [61, 62]. Low- for 30–40 s in CPAP mode with a RR of 0) or a stepwise ering tidal volume to reduce driving pressure resulted increase in PEEP followed by a decremental PEEP titra- in the greatest benefit in patients with low lung compli- tion. The physiologic rationale of a recruitment ance. Optimizing ventilator settings to achieve a driving maneuver is to provide static or dynamic inflation at pressure < 15 may be the preferred target [2, 58, 59, 63]. very high pressures for a short period of time to recruit There are ongoing clinical trials to investigate a driving alveolar units to participate in gas exchange and improve pressure-driven approach to ventilator management. respiratory system compliance. Most lung recruitment occurs in the first 10 s of sustained inflation, while hemo- Airway pressure release ventilation dynamic instability occurs after 10 s. The effects of Airway pressure release ventilation (APRV) is an alterna- increasing PEEP likely stabilize after 11–20 breaths. tive mode of mechanical ventilation used to treat refrac- Recruitment maneuvers have been shown to improve tory hypoxemia and ARDS. APRV is a pressure-limited oxygenation, however, have not been shown to improve mode that cycles between two levels of CPAP. A higher mortality, and may actually be injurious [50–54]. In airway pressure (P-high) is set for a certain time (T-high) one study, 22% of patients who received recruitment and a lower airway pressure (P-low) (often set at 0 cm maneuvers developed non-sustained hypotension and/ ­H2O) is set for a shorter time (T-low). APRV utilizes an or hypoxemia [54, 55]. In the ART trial, patients received inverted inspiration:expiration ratio, as the majority of a 4-min recruitment maneuver in a stepwise fashion spontaneous breathing is accomplished during T-high, (PC with PEEP at 25 cm ­H2O for 1 min, 35 cm ­H2O for with the higher pressure P-high theoretically allowing for 1 min, and 45 cm H ­ 2O for 2 min) followed by decremen- recruitment of collapsed alveoli, and T-low allowing for tal PEEP. The recruitment maneuver strategy was modi- ventilation and complete exhalation [64–66]. The pro- fied mid-enrollment due to 3 cardiac arrests observed posed benefits to APRV include allowing for spontaneous in the experimental arm, and overall the experimental breathing, decreased work of breathing, and less dyssyn- arm showed increased mortality. There is signifi- chrony (and therefore less use of sedatives and paralyt- cant heterogeneity amongst studies evaluating recruit- ics). It is also thought that higher mean airway pressures ment maneuvers, making meta-analyses challenging to may improve oxygenation when compared to more con- interpret. Though some patients may show improved ventional modes of mechanical ventilation. While oxygenation with a recruitment maneuver, evidence sug- APRV may increase mean airway pressures there is less gests that there is no mortality benefit, and there may control over tidal volume and minute ventilation. Some be associated harm. While not recommended routinely, patients may also require deep sedation and/or paralysis, select patients may respond favorably. If used, a stepwise thereby eliminating spontaneous breathing, compromis- increase in PEEP followed by decremental PEEP titration ing adequate ventilation. These issues may be overcome may be more effective , though more modest levels of using time-controlled adaptive ventilation (TCAV), Grotberg et al. Critical Care (2023) 27:289 Page 6 of 15 where T-low is set to terminate at 75% of the expiratory. However, in a meta-analysis of four studies (1552 flow peak, maintaining adequate alveolar inflation during patients total) comparing HFOV to conventional IMV, the release phase. If a patient requires a higher minute the association of HFOV on 30-day mortality varied ventilation, T-high is reduced to increase the frequency with severity of hypoxemia: For patients with severe of releases while T-low remains set based on expira- ARDS, HFOV was associated with improved mortal- tory flow dynamics [67, 68]. Despite its use in ARDS, ity, whereas in patients with mild-to-moderate ARDS high quality evidence favoring APRV is lacking, and the (P/F > 100), HFOV was associated with worsened mortal- available studies reported mixed results. A systematic ity. Though societies recommend against routinely review and meta-analysis of eight studies found that use using HFOV in patients with moderate-to-severe ARDS of APRV in critically ill adults with acute hypoxemic res- , there may be select patients with severe ARDS who piratory failure was associated with improved mortality benefit. and oxygenation, although the studies were small, single- center studies. Another systematic review and meta- Mechanical power analysis of six studies with 375 patients found that APRV Mechanical power is the mechanical energy delivered was associated with improved oxygenation and decreased from the ventilator to the respiratory system and has ICU length of stay, but had no effect on mortality. been hypothesized as a unifying driver of VILI. More recently, a randomized controlled trial of 90 adult Patients with severe ARDS receive mechanical ventila- patients with COVID-19 related ARDS compared APRV tion with higher mechanical power than mild or moder- to conventional low tidal volume ventilation and found ate ARDS, though it is unclear if this is correlative or that APRV was not associated with improvements in causative of further lung injury. The power equation ventilator-free days or mortality. Larger, multicenter, tidal volume, elastance, inspiratory and expiratory time, randomized studies are needed to further clarify if APRV airway resistance, PEEP, and respiratory rate. This math- is beneficial in patients with severe ARDS (or in ARDS ematical representation, however, does not necessarily subgroups) compared with conventional ventilation. address how energy is distributed to the lung paren- chyma versus the respiratory system as a whole [80, 81]. High frequency oscillatory ventilation Other simplified versions of the mechanical power equa- High frequency oscillatory ventilation (HFOV) is a mode tion have been derived using parameters easily measured of IMV that employs a constant airway pressure with at the bedside. The most clinically useful equation is oscillations at extreme respiratory frequencies (e.g., MP = 0.098 × Vt × RR × Ppeak − 12 DP , where MP is 5–15 Hz or 300–900 breaths per minute), delivering mechanical power, Vt is tidal volume, RR is respiratory tidal volumes well below that of anatomical dead space rate, Ppeak is peak pressure, and DP is the driving pres- [71, 72]. Gas exchange is by convection and diffusion: In sure. Using this representation, an analysis of two cohorts large airways, convection predominates, where gas flow of 8207 patients with ARDS showed that higher mechan- is dependent on turbulent flow, bulk convection, and cen- ical power (> 17.0 J/min) was independently associated tral airway oscillatory pressure. In the lung periphery and with higher ICU-, hospital- and 30-day mortality and alveolar units, diffusion predominates, where gas flow is decreased ventilator-free days, even in patients receiving dependent on Taylor dispersion, collateral ventilation, low tidal volumes. Using a simpler model, Costa Pendelluft, and cardiogenic mixing. Higher oscillatory et al. also showed that driving pressure and RR pressures recruit atelectatic alveoli but are dampened in ((4 × DP) + RR ) was equivalent to mechanical power aerated alveoli. In the small airways and mid-lung zones, and associated with mortality. This suggests that both convention and diffusion direct gas flow and are driving pressure and RR may be the more important vari- dependent on turbulence, peripheral airways resistance, ables of VILI. Pendelluft, and asymmetric inspiratory and expiratory velocity profiles. While HFOV was previously con- Proning sidered a rescue mode of ventilation for severe ARDS, its Prone ventilation improves oxygenation and ventilatory use has fallen out of favor. Previous studies found mixed mechanics in many patients with severe ARDS [84–87]. results among patients with moderate-to-severe ARDS There is often significant heterogeneity of pulmonary [73–75], and a larger trial of 548 patients with moderate- edema, consolidation, and atelectasis affecting dorsal to-severe ARDS demonstrated higher in-hospital mor- lung regions. Proning improves heterogeneity allowing tality in patients randomized to HFOV compared with for increased lung recruitment, ventilation-perfusion conventional high PEEP/low tidal volume ventilation matching, and decreased overdistension and lung stress. Grotberg et al. Critical Care (2023) 27:289 Page 7 of 15 These physiologic effects have been demonstrated in ani- while an E/E’ ratio < 8 is associated with normal left-sided mal models using electrical impedance tomography (EIT) filling pressures, particularly when coupled with lung [88, 89]. The PROSEVA trial is the most notable study of ultrasonography [97, 98]. Stroke volume and cardiac out- early proning in patients with moderate-to-severe ARDS put can be evaluated using the left ventricular outflow (P/F < 150, ­FIO2 ≥ 60%). 28-day mortality in the proning tract velocity time integral (LVOT VTI) and diameter group was 16% compared to 32.8% in the supine group [96, 99]. IVC respiratory variation is a poor predictor of (p < 0.001), and 90-day mortality in the proning group volume-responsiveness in patients with severe ARDS as was 23.6% compared to 41% (p < 0.001). The average this method was validated in patients receiving > 8 cc/kg duration per proning session was 17 h and each patient IBW tidal volumes. Respiratory variation of LVOT VTI underwent 4 proning sessions on average. Meta-anal- presents a better indicator of predicting fluid responsive- yses of proning trials have shown improved oxygenation ness, where a difference in 15 to 20% is associated with and improved mortality when proning sessions last ≥ 12 h fluid responsiveness [96, 100]. [90–92]. Proning is generally indicated in moderate-to- severe ARDS (P/F < 150) after appropriate ventilator opti- Glucocorticoids mization. While paralysis may help to facilitate proning The administration of empiric steroids for severe ARDS safely, it is not required. In PROSEVA, patients continued has remained controversial and clinical trial results have proning sessions until supine oxygenation improved to varied significantly. One trial conducted found moderate- a P/F ≥ 150 with a PEEP ≤ 10 cm ­H2O and an F ­ iO2 ≤ 0.6; dose methylprednisolone significantly reduced duration therefore, smaller improvements in patient oxygenation of mechanical ventilation, length of ICU stay, and ICU should not necessarily halt proning. If oxygenation does mortality. However, a larger study in 2006 by the not improve, patients may still benefit from improved ARDS Network showed no clinical benefit in patients respiratory mechanics and reduced lung stress, as the treated with steroids within 7 days of ARDS onset, and mortality benefit was not directly linked to improved increased mortality in patients treated 14 days after oxygenation. This may suggest static compliance, ARDS onset. More recently, the DEXA-ARDS trial rather than P/F, is the more physiologically relevant studied patients with moderate-to-severe ARDS and proning endpoint. However, robust data are lacking found that patients who received dexamethasone expe- to support compliance-guided proning strategies. rienced more ventilator-free days and lower mortality. Dexamethasone has also been shown to improve Fluid management overall mortality in patients with hypoxemia due to mod- Acute lung injury during ARDS may be exacerbated by erate or severe COVID-19 pneumonia [104–106]. fluid overload. A landmark trial conducted by the ARDS Different ARDS subphenotypes display differing Network (FACTT) compared two fluid management responses to corticosteroid treatment. A latent class strategies in ARDS: a “conservative” strategy and a “lib- analysis of the ARMA and ALVEOLI trials revealed the eral” strategy. Treatment protocols consisted of existence of two distinct phenotypes: (1) hyperinflamma- combinations of IV fluids, diuretics, or inotropes based tory and (2) hypoinflammatory. The hyperinflam- on the CVP or PAOP, cardiac output, and the presence matory phenotype exhibits a higher overall mortality, or absence of shock and oliguria. While there was no and in a retrospective analysis of COVID-19 ARDS, had effect on mortality, patients treated with conservative improved mortality with steroids, while the hypoinflam- fluid strategy (goal CVP < 4 mm Hg and PAOP < 8 mm matory group had worse mortality with steroids. Hg in the presence of effective circulation) had less fluid While the empiric use of glucocorticoids remains contro- accumulation and increased ventilator-free and ICU-free versial in all patients with severe ARDS, there are likely days. select ARDS subgroups that derive benefit. Non-invasive methods, namely point-of-care ultra- sonography (POCUS), can also be used to monitor Neuromuscular blockade hemodynamics and intravascular volume status. Venous Neuromuscular blockade (NMB) improves oxygena- congestion may be demonstrated by inferior vena cava tion via several mechanisms. Paralysis decreases oxy- (IVC) dilation with poor respiratory variability and gen consumption, eliminates ventilator dyssynchrony, S-wave reversal in the hepatic veins while low static fill- and improves thoracopulmonary compliance. The ing pressures may be seen with a small IVC and a small, ACURASYS trial in 2010 demonstrated a mortality ben- hyperdynamic LV cavity [95, 96]. An E/E’ ratio > 15 is efit with 48 h of NMB with cisatracurium in patients with associated with increased left-sided filling pressures, moderate-to-severe ARDS (P/F < 150). The larger Grotberg et al. Critical Care (2023) 27:289 Page 8 of 15 multicenter ROSE trial in 2019 found no significant mor- ventilation-perfusion matching and may be used in tality benefit using NMB in moderate-to-severe ARDS patients with refractory hypoxemia [116, 117]. However,. However, patients already receiving NMB at the they do not improve mortality [116–119]. time of enrollment were excluded and it is possible that a subset of patients still benefit from NMB when deemed Veno‑venous extracorporeal membrane beneficial by clinician judgment. Additionally, in contrast oxygenation to ACURASYS, the ROSE control arm received less seda- V-V ECMO provides extracorporeal gas exchange in tion than the NMB group, which has been previously patients with refractory respiratory failure , and associated with improved ICU outcomes. While it plays a critical role in the care of select patients with is evident that NMB improves oxygenation, it is contro- severe ARDS, though the selection criteria and timing of versial whether it confers a mortality benefit. its use remain controversial. Studies have shown a wide Prolonged use of NMB increases the risk of neuro- array of outcomes when comparing ECMO to conven- muscular weakness and muscle loss, pressure injuries, tional management [121–123]. Two notable prospec- and deep vein thromboses, and requires deep sedation tive randomized trials for V-V ECMO in ARDS were the which can increase delirium and neurocognitive impair- CESAR trial and EOLIA trial. CESAR enrolled subjects ment and decrease ventilator-free days [112, 113]. When with a Murray score ≥ 3 or pH < 7.2 despite optimal ven- using NMB agents, train-of-four (TOF) monitoring may tilator settings. CESAR randomized patients to trans- be used to titrate to the lowest effective dose. Deep fer to an ECMO center, rather than ECMO itself. Of the sedation is also required during NMB and may be titrated patients that were transferred, 20% did not receive ECMO using bispectral index (BIS) to a goal of 40 to 60. (instead they received optimized conventional mechani- cal ventilation), of which 82% survived. There was an Inhaled pulmonary vasodilators overall survival benefit (63% versus 47%, p = 0.03) when Several trials have investigated the role of inhaled pul- transferred to an ECMO center. EOLIA enrolled monary vasodilators in ARDS, notably iNO and inhaled subjects with a P/F < 50 for > 3 h, P/F < 80 for > 6 h (with prostaglandins. Inhaled pulmonary vasodilators improve ­FIO2 > 80%) with optimal ventilator settings and adjunc- oxygenation and P/F ratio in most patients by improving tive measures (paralysis, proning, inhaled pulmonary Fig. 3 V-V ECMO considerations. A flowchart illustrating indications for veno-venous ECMO, initial ventilator management, monitoring of right ventricular function and contraindications to ECMO Grotberg et al. Critical Care (2023) 27:289 Page 9 of 15 vasodilators), or pH < 7.25 and p ­ CO2 > 60 while maintain- titrate PEEP understanding this nuance. Patients requir- ing PPlat < 32 and maximum RR 35 (Fig. 3). Though there ing V-V ECMO who develop ACP may be considered for was a non-significant trend toward improved mortality in circuit adjustment such as RV assist ECMO (OxyRVAD), the ECMO arm (p = 0.09), the study had an intention-to- where a return cannula is placed in the main pulmonary treat design and 28% of the patients in the control group artery under transesophageal guidance to bypass the fail- crossed over to receive salvage ECMO therapy, of which ing RV [149, 150] or veno-arterial venous ECMO (Fig. 4). 43% survived. The subgroup that benefitted most from ECMO were patients with excessive ventilatory ARDS survivorship pressures and refractory respiratory acidosis. A post-hoc Survivors of severe ARDS are at increased risk for physi- Bayesian analysis and meta-analysis suggested ECMO cal and neurocognitive sequelae that may persist for may provide a ~ 10% mortality benefit [126, 127]. years. Common complications include vocal cord dys- While optimal ventilator settings for patients on V-V function and tracheal stenosis due to endotracheal tube ECMO are not clear, the use of ECMO allows for “lung pressure-related trauma, skin pressure injuries, frailty, rest” with dramatic reductions in driving pressure, PPlat, neuromyopathies, and cognitive dysfunction. One and mechanical power [128–132], which may reduce study of 109 ARDS survivors found persistent functional ongoing VILI [120, 124, 128, 131, 133, 134] (Fig. 3). disability at one year after hospital discharge including Higher PEEP and lower driving pressure while on ECMO abnormal pulmonary function testing, reduced 6-min has been associated with improved mortality [135–137] walk distance, and reduced health-related quality of life. and decreased cytokine release [138–141]. Optimal PEEP Moreover, ARDS severity predicted exercise capacity at has been evaluated in small cohorts using EIT demon- 6 months. Lower health-related quality of life was strating that most patients require a PEEP of 10–15 cm also seen in ECMO survivors. Muscular weakness ­H2O to minimize overdistension and atelectasis and is common and affects long-term functioning. Acute improve compliance [142–144]. PEEP can also be titrated skeletal muscle wasting occurs within one week, and at the bedside to achieve optimal compliance. is more pronounced in patients with multiorgan failure. Patients who received corticosteroids and/or NMB Acute cor pulmonale are at higher risk for critical illness myopathy , and Acute cor pulmonale (ACP) is common in severe ARDS, physical decline has been shown to persist at 5 years after with an estimated incidence of 25% , but may be discharge. higher in COVID-19 (~ 38%). The etiology of ACP Neurocognitive dysfunction is also common after is often multifactorial including pulmonary vascular dys- ARDS and data suggests and > 50% of survivors have function, regional hypoxemia with pulmonary vasocon- persistent cognitive impairment at one year [155, 156]. striction, and high mean airway pressures in the setting of Psychiatric morbidities, including depression, post-trau- poor lung compliance. Severe ACP, as defined by a right matic stress disorder (PTSD), anxiety and suicidality also ventricular-to-left ventricular (RV/LV) ratio ≥ 1 with RV occur at higher frequencies after ARDS. septal dyskinesia, is associated with even higher mortal- ity. Patients with severe ARDS should be serially Conclusion monitored for the development of RV dysfunction via Severe ARDS carries a high morbidity and mortality, echocardiography or POCUS. If RV dysfunction devel- and refractory hypoxemia can prove challenging to man- ops, careful attention should be placed to intravascular age. Low tidal volume ventilation, proning, conservative volume status and cardiac output. Inhaled pulmonary fluid management, and individualized PEEP titration vasodilators (e.g., iNO, epoprostenol, or systemic vasodi- to minimize driving pressure improve outcomes and lators (e.g., sildenafil), may be utilized to reduce pulmo- are the mainstays of severe ARDS therapy. Optimizing nary pressures. Inotropic agents may be used to augment ventilator-lung mechanics as they relate to mechanical cardiac output. The effects of PEEP on the pulmonary power and driving pressure may further induce second- vascular resistance (PVR) and RV function may vary. ary VILI. Patients with refractory hypoxemia may benefit The PVR-to-lung volume curve is generally U-shaped, from inhaled pulmonary vasodilators and neuromuscu- with the lowest PVR at functional residual capacity. lar blockade, although these interventions have not been Higher PEEP may induce more West zone 1 and 2 physi- consistently shown to improve mortality. V-V ECMO ology resulting in increased PVR and RV dysfunction. likely confers a small (~ 10%) mortality benefit in a select However, hypoxic vasoconstriction in the pulmonary subset of patients and can be considered on a case-by- circulation also increases PVR, which may be addressed case basis. with higher PEEP [47, 148]. The clinician should carefully Grotberg et al. Critical Care (2023) 27:289 Page 10 of 15 Fig. 4 V-V ECMO configurations. A schematic illustrating the reconfiguration of conventional V-V ECMO to either right ventricular assist ECMO (OxyRVAD) or veno-arterial venous ECMO (V-AV ECMO). Adapted from “Extracorporeal Membrane Oxygenation (ECMO),” by BioRender.com (2023). Retrieved from https://​app.​biore​nder.​com/​biore​nder-​templ​ates Abbreviations PL Transpulmonary pressure ACP Acute cor pulmonale P-low The set low pressure during airway pressure release ventilation AI Asynchrony index POCUS Point-of-care ultrasonography APRV Airway pressure release ventilation Ppeak Peak pressure ARDS Acute respiratory distress syndrome PPl Pleural pressure CRS Compliance of the respiratory system Pplat Plateau pressure CVP Central venous pressure PTSD Post-traumatic stress disorder DO2 Delivery of oxygen PVR Pulmonary vascular resistance DP Driving pressure RR Respiratory rate EIT Electrical impedance tomography RV Right ventricle FiO2 Fraction of inspired oxygen SI Stress index HFOV High frequency oscillatory ventilation T-low The set time during the low pressure of airway pressure release IBW Ideal body weight ventilation ICU Intensive care unit T-high The set time during the high pressure of airway pressure release iNO Inhaled nitric oxide ventilation IVC Inferior vena cava V-AV ECMO Veno-venoarterial extracorporeal membrane oxygenation LV Left ventricle VILI Ventilator-induced lung injury LVOT VTI Left ventricular outflow tract velocity time integral Vt Tidal volume MP Mechanical power V-V ECMO Veno-venous extracorporeal membrane oxygenation NMB Neuromuscular blockade OxyRVAD Right ventricular assist extracorporeal membrane oxygenation Author contributions Pao Airway pressure JG and BK conceptualized, wrote and edited the entirety of manuscript. DR PaO2 Partial pressure of oxygen in arterial blood wrote select sections of the manuscript and edited the entirety of the manu- PAOP Pulmonary artery occlusion pressure script. All authors approved the final manuscript. PEEP Positive end expiratory pressure PEEPODCL PEEP with least overdistended and collapsed lung Funding Pes Esophageal pressure The funding was provided by National Institutes of Health (Grant number P-high The set high pressure during airway pressure release ventilation T32HL007317). Grotberg et al. Critical Care (2023) 27:289 Page 11 of 15 Availability of data and materials 15. Marini JJ, MacIntyre N. Point: Is pressure assist-control preferred over Not applicable. volume assist-control mode for lung protective ventilation in patients with ARDS? Yes No Chest. 2011;140(2):286–90. 16. MacIntyre N. Counterpoint: Is pressure assist-control preferred over Declarations volume assist-control mode for lung protective ventilation in patients with ARDS? No. Chest [Internet]. 2011;140(2):290–2. https://​doi.​org/​10.​ Ethics approval and consent to participate 1378/​chest.​11-​1052. Not applicable. 17. Singh G, Chien C, Patel S. Pressure Regulated Volume Control (PRVC): set it and forget it? Respir Med Case Rep. 2018;2020(29): 100822. Consent for publication 18. Romano MLP, Maia IS, Laranjeira LN, Damiani LP, Paisani DDM, Borges Not applicable. MDC, et al. Driving pressure-limited strategy for patients with acute respiratory distress syndrome a pilot randomized clinical trial. Ann Am Competing interests Thorac Soc. 2020;17(5):596–604. The authors declare that they have no competing interests. 19. Hirshberg EL, Majercik S. Targeting driving pressure for the manage- ment of ards.isn’t it just very low tidal volume ventilation? Ann Am Thorac Soc. 2020;17(5):557–8. Received: 29 March 2023 Accepted: 10 July 2023 20. Gattinoni L, Tonetti T, Cressoni M, Cadringher P, Herrmann P, Moerer O, et al. Ventilator-related causes of lung injury: the mechanical power. Intensive Care Med. 2016;42(10):1567–75. 21. Thille AW, Rodriguez P, Cabello B, Lellouche F, Brochard L. Patient-venti- lator asynchrony during assisted mechanical ventilation. Intensive Care References Med. 2006;32:1515–22. 1. Ashbaugh D, Bigelow DB, Petty T, Levine B. Acute respiratory distress in 22. Blanch L, Villagra A, Sales B, Montanya J, Lucangelo U, Luján M, et al. adults. Lancet. 1967;290(7511):319–23. Asynchronies during mechanical ventilation are associated with mor- 2. Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemi- tality. Intensive Care Med. 2015;41(4):633–41. ology, patterns of care, and mortality for patients with acute respiratory 23. Gilstrap D, MacIntyre N. Patient-ventilator interactions implications for distress syndrome in intensive care units in 50 countries. JAMA J Am clinical management. Am J Respir Crit Care Med. 2013;188(9):1058–68. Med Assoc. 2016;315(8):788–800. 24. Pham T, Telias I, Piraino T, Yoshida T, Brochard LJ. Asynchrony conse- 3. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. quences and management. Crit Care Clin. 2018;34(3):325–41. 2020;383(25):2451–60. 25. Dianti J, Tisminetzky M, Ferreyro BL, Englesakis M, Del Sorbo L, Sud S, 4. Palanidurai S, Phua J, Chan YH, Mukhopadhyay A. P/FP ratio: incor- et al. Association of positive end-expiratory pressure and lung recruit- poration of PEEP into the P ­ aO2/FiO2 ratio for prognostication and ment selection strategies with mortality in acute respiratory distress classification of acute respiratory distress syndrome. Ann Intensive Care. syndrome a systematic review and network meta-analysis. Am J Respir 2021;11(1):1–9. Crit Care Med. 2022;205(11):1300–10. 5. Riviello ED, Kiviri W, Twagirumugabe T, Mueller A, Banner-Goodspeed 26. Goligher EC, Kavanagh BP, Rubenfeld GD, Adhikari NKJ, Pinto R, Fan VM, Officer L, et al. Hospital incidence and outcomes of the acute E, et al. Oxygenation response to positive end-expiratory pressure respiratory distress syndrome using the Kigali modification of the Berlin predicts mortality in acute respiratory distress syndrome: a second- definition. Am J Respir Crit Care Med. 2016;193(1):52–9. ary analysis of the LOVS and express trials. Am J Respir Crit Care Med. 6. Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfeld DA, Ware LB. 2014;190(1):70–6. Comparison of the ­SpO2/FIO2 ratio and the P ­ aO2/FIO2 ratio in patients 27. Briel M, Meade M, Mercat A. Higher vs lower positive end-expiratory with acute lung injury or ARDS. Chest. 2007;132(2):410–7. pressure in patients with acute lung injury. JAMA J Am Med Assoc. 7. Pandharipande P, Shintani A, Hagerman H, St Jacques P, Rice T, Sanders 2010;303(9):865–73. N, et al. Derivation and validation of S­ po2/Fio2 ratio to impute for ­Pao2/ 28. Santa Cruz R, Villarejo F, Irrazabal C, Ciapponi A. High versus low positive Fio2 ratio in the respiratory component of the Sequential Organ Failure end-expiratory pressure (PEEP) levels for mechanically ventilated adult Assessment score. Crit Care Med. 2009;37(4):1317–21. patients with acute lung injury and acute respiratory distress syndrome. 8. Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler Cochrane Database Syst Rev. 2021;2021(3):1–47. A. Ventilation with lower tidal volumes as compared with traditional 29. Villar J, Kacmarek RM, Pérez-Méndez L, Aguirre-Jaime A. A high positive tidal volumes for acute lung injury and the acute respiratory distress end-expiratory pressure, low tidal volume ventilatory strategy improves syndrome. N Engl J Med. 2000;342(18):1301–8. outcome in persistent acute respiratory distress syndrome: a rand- 9. Guérin C, Reignier J, Richard J-C, Beuret P, Gacouin A, Boulain T, et al. omized, controlled trial. Crit Care Med. 2006;34(5):1311–8. Prone positioning in severe acute respiratory distress syndrome. N Engl 30. Brower R, Lanken P, MacIntyre N, Matthay M, Morris A, Ancukiewicz J Med. 2013;368(23):2159–68. M, et al. Higher versus lower positive end-expiratory pressures in 10. Wiedemann H, Wheeler A, Bernard G, Thompson B, Hayden D, DeBois- patients with the acute respiratory distress syndrome. N Engl J Med. blanc B, et al. Comparison of two fluid-management strategies in acute 2004;351(4):327–36. lung injury. N Engl J Med. 2006;354(24):2564–75. 31. Walkey AJ, Del Sorbo L, Hodgson CL, Adhikari NKJ, Wunsch H, Meade 11. Petrucci N, De Feo C. Lung protective ventilation strategy for the MO, et al. Higher PEEP versus lower PEEP strategies for patients with acute respiratory distress syndrome. Cochrane Database Syst Rev. acute respiratory distress syndrome: a systematic review and meta- 2013;2013(2):1–25. analysis. Ann Am Thorac Soc. 2017;14:S297-303. 12. Walkey AJ, Goligher EC, Del Sorbo L, Hodgson CL, Adhikari NKJ, Wunsch 32. Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, et al. H, et al. Low tidal volume versus non–volume-limited strategies for Ventilation strategy using low tidal volumes, recruitment maneuvers, patients with acute respiratory distress syndrome: a systematic review and high positive end-expiratory pressure for acute lung injury and and meta-analysis. Ann Am Thorac Soc. 2017;14:S271–9. acute respiratory distress syndrome: a randomized controlled trial. 13. Amato MBP, Valente Barbas CS, Medeiros DM, Magaldi RB, De Pinto JAMA. 2008;299(6):637–45. SG, Lorenzi-Filho G, et al. Effect of a protective ventilation strategy on 33. Mercat A, Richard J-CM, Jaber S, Osman D, Diehl J-L, Lefrant J, et al. Posi- mortality in the acute respiratory distress syndrome. N Engl J Med. tive end-expiratory pressure setting in adults with acute lung injury and 1998;338:347–54. acute respiratory distress syndrome. JAMA. 2008;299(6):646–55. 14. Chacko B, Peter J V., Tharyan P, John G, Jeyaseelan L. Pressure-controlled 34. Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA. versus volume-controlled ventilation for acute respiratory failure due Subphenotypes in acute respiratory distress syndrome: Latent class to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). analysis of data from two randomised controlled trials. Lancet Respir Cochrane Database Syst Rev. 2015;2017(6):1–48. Med. 2014;2(8):611–20. Grotberg et al. Critical Care (2023) 27:289 Page 12 of 15 35. Hess DR. Recruitment maneuvers and PEEP titration. Respir Care. 55. Fan E, Checkley W, Stewart TE, Muscedere J, Lesur O, Granton JT, et al. 2015;60(11):1688–704. Complications from recruitment maneuvers in patients with acute lung 36. Grasso S, Stripoli T, De Michele M, Bruno F, Moschetta M, Angelelli injury: Secondary analysis from the lung open ventilation study. Respir G, et al. ARDSnet ventilatory protocol and alveolar hyperinflation: Care. 2012;57(11):1842–9. role of positive end-expiratory pressure. Am J Respir Crit Care Med. 56. Cavalcanti AB, Suzumura ÉA, Laranjeira LN, De Moraes PD, Damiani 2007;176(8):761–7. LP, Guimarães HP, et al. Effect of lung recruitment and titrated Positive 37. Huang Y, Yang Y, Chen Q, Liu S, Liu L, Pan C, et al. Pulmonary acute End-Expiratory Pressure (PEEP) vs low PEEP on mortality in patients with respiratory distress syndrome: positive end-expiratory pressure titration acute respiratory distress syndrome—a randomized clinical trial. JAMA needs stress index. J Surg Res. 2013;185(1):347–52. J Am Med Assoc. 2017;318(14):1335–45. 38. Zhao Z, Chang MY, Chang MY, Gow CH, Zhang JH, Hsu YL, et al. Positive 57. Marini JJ. Recruitment by sustained inflation: time for a change. Inten- end-expiratory pressure titration with electrical impedance tomogra- sive Care Med. 2011;37(10):1572–4. phy and pressure–volume curve in severe acute respiratory distress 58. Amato MBP, Meade MO, Slutsky AS, Brochard L, Costa ELV, Schoenfeld syndrome. Ann Intensive Care. 2019;9(1):1–9. DA, et al. Driving pressure and survival in the acute respiratory distress 39. He H, Chi Y, Yang Y, Yuan S, Long Y, Zhao P, et al. Early individualized syndrome. N Engl J Med. 2015;372(8):747–55. positive end-expiratory pressure guided by electrical impedance 59. Urner R, Jüni P, Hansen B, Wettstein MS, Ferguson ND, Fan E. Time-var- tomography in acute respiratory distress syndrome: a randomized ying intensity of mechanical ventilation and mortality in patients with controlled clinical trial. Crit Care. 2021;25(1):1–11. acute respiratory failure: a registry-based, prospective cohort study. 40. Spinelli E, Kircher M, Stender B, Ottaviani I, Basile MC, Marongiu I, Lancet Respir Med. 2020;8:905–13. et al. Unmatched ventilation and perfusion measured by electrical 60. Aoyama H, Pettenuzzo T, Aoyama K, Pinto R, Englesakis M, Fan E. Asso- impedance tomography predicts the outcome of ARDS. Crit Care. ciation of driving pressure with mortality among ventilated patients 2021;25(1):1–12. with acute respiratory distress syndrome: a systematic review and 41. Jimenez JV, Weirauch AJ, Culter CA, Choi PJ, Hyzy RC. Electrical imped- meta-analysis. Crit Care Med. 2018;46(2):300–6. ance tomography in acute respiratory distress syndrome management. 61. Goligher EC, Costa ELV, Yarnell CJ, Brochard LJ, Stewart TE, Tomlinson Crit Care Med. 2022;50(8):1210–23. G, et al. Effect of lowering vt on mortality in acute respiratory distress 42. Baedorf Kassis E, Talmor D. Clinical application of esophageal manom- syndrome varies with respiratory system elastance. Am J Respir Crit etry: how I do it. Crit Care. 2021;25(1):4–7. Care Med. 2021;203(11):1378–85. 43. Talmor D, Sarge T, Malhotra A, O’Donnell C, Ritz R, Lisbon A, et al. 62. Bihari S, Thompson BT, Bersten AD. Do more injured lungs need more Mechanical ventilation guided by esophageal pressure in acute lung protection? Let’s test it. Am J Respir Crit Care Med. 2021;203(11):1334–6. injury. N Engl J Med. 2008;359(20):2095–104. 63. Urner M, Jüni P, Rojas-Saunero L, Hansen B, Brochard L, Ferguson N, 44. Beitler JR, Sarge T, Banner-Goodspeed VM, Gong MN, Cook D, Novack et al. Limiting dynamic driving pressure in patients requiring mechani- V, et al. Effect of titrating positive end-expiratory pressure (PEEP) with cal ventilation. Crit Care Med. 2023;51(7):861–71. an esophageal pressure-guided strategy vs an empirical high PEEP-Fio2 64. Othman F, Alsagami N, Alharbi R, Almuammer Y, Alshahrani S, Ismaeil T. strategy on death and days free from mechanical ventilation among The efficacy of airway pressure release ventilation in acute respiratory patients with acute respiratory distress syndrome: A. JAMA J Am Med distress syndrome adult patients: a meta-analysis of clinical trials. Ann Assoc. 2019;321(9):846–57. Thorac Med. 2021;16(3):245–52. 45. Sarge T, Baedorf-Kassis E, Banner-Goodspeed V, Novack V, Loring 65. Cheng J, Ma A, Dong M, Zhou Y, Wang B, Xue Y, et al. Does airway pres- SH, Gong MN, et al. Effect of esophageal pressure–guided positive sure release ventilation offer new hope for treating acute respiratory end-expiratory pressure on survival from acute respiratory distress distress syndrome? J Intensive Med. 2022;2(4):241–8. syndrome: a risk-based and mechanistic reanalysis of the EPVent-2 trial. 66. Hager DN. Airway pressure release ventilation in acute hypox- Am J Respir Crit Care Med. 2021;204(10):1153–63. emic respiratory failure: curb your enthusiasm. Crit Care Med. 46. Chen L, Del Sorbo L, Grieco DL, Junhasavasdikul D, Rittayamai N, Soli- 2019;47(12):1817–8. man I, et al. Potential for lung recruitment estimated by the recruit- 67. Habashi NM. Other approaches to open-lung ventilation: airway pres- ment-to-inflation ratio in acute respiratory distress syndrome a clinical sure release ventilation. Crit Care Med. 2005;33(3):S228–40. trial. Am J Respir Crit Care Med. 2020;201(2):178–87. 68. Kollisch-Singule M, Andrews P, Satalin J, Gatto LA, Nieman GF, Habashi 47. Luecke T, Pelosi P. Clinical review: positive end-expiratory pressure and NM. The time-controlled adaptive ventilation protocol: Mechanistic cardiac output. Crit Care. 2005;9(6):607–21. approach to reducing ventilator-induced lung injury. Eur Respir Rev. 48. Arnal JM, Paquet J, Wysocki M, Demory D, Donati S, Granier I, et al. Opti- 2019;28(152):1–12. mal duration of a sustained inflation recruitment maneuver in ARDS 69. Lim J, Litton E. Airway pressure release ventilation in adult patients patients. Intensive Care Med. 2011;37(10):1588–94. with acute hypoxemic respiratory failure: a systematic review and meta- 49. Katz J, Ozanne G, Zinn S, Fairley H. Time course and mechanisms of analysis. Crit Care Med. 2019;47(12):1794–9. lung-volume increase with PEEP in acute pulmonary failure. Anesthesi- 70. Ibarra-Estrada MA, García-Salas Y, Mireles-Cabodevila E, López-Pulgarín ology. 1981;54(1):9–16. JA, Chávez-Peña Q, García-Salcido R, et al. Use of airway pressure release 50. Brower RG, Morris A, MacIntyre N, Matthay MA, Hayden D, Thompson ventilation in patients with acute respiratory failure due to COVID-19: BT, et al. Effects of recruitment maneuvers in patients with acute lung results of a single-center randomized controlled trial. Crit Care Med. injury and acute respiratory distress syndrome ventilated with high 2022;50(4):586–94. positive end-expiratory pressure. Crit Care Med. 2003;31(11):2592–7. 71. Meyers M, Rodrigues N, Ari A. High-frequency oscillatory ventilation: a 51. Hodgson C, Ec G, Me Y, Jl K, Ae H, Romero L, et al. Recruitment manoeu- narrative review. Can J Respir Ther. 2019;55(1):40–6. vres for adults with acute respiratory distress syndrome receiving 72. Miller AG, Tan HL, Smith BJ, Rotta AT, Lee JH. The physiological basis of mechanical ventilation (Review). Cochrane Database Syst Rev. 2018. high-frequency oscillatory ventilation and current evidence in adults 52. Suzumura EA, Figueiró M, Normilio-Silva K, Laranjeira L, Oliveira C, Bue- and children: a narrative review. Front Physiol. 2022;13(April):1–17. hler AM, et al. Effects of alveolar recruitment maneuvers on clinical out- 73. Derdak S, Mehta S, Stewart TE, Smith T, Rogers M, Buchman TG, et al. comes in patients with acute respiratory distress syndrome: a system- High-frequency oscillatory ventilation for acute respiratory distress atic review and meta-analysis. Intensive Care Med. 2014;40(9):1227–40. syndrome in adults: a randomized, controlled trial. Am J Respir Crit Care 53. Xi XM, Jiang L, Zhu B. Clinical efficacy and safety of recruitment maneu- Med. 2002;166(6):801–8. ver in patients with acute respiratory distress syndrome using low tidal 74. Young D, Lamb S, Shah S, MacKenzie I, Tunnicliffe W, Lall R, et al. High- volume ventilation: a multicenter randomized controlled clinical trial. frequency oscillation for acute respiratory distress syndrome. N Engl J Chin Med J (Engl). 2010;123(21):3100–5. Med. 2013;368:806–13. 54. Meade MO, Cook DJ, Griffith LE, Hand LE, Lapinsky SE, Stewart TE, et al. 75. Bollen CW, van Well GTJ, Sherry T, Beale RJ, Shah S, Findlay G, et al. A study of the physiologic responses to a lung recruitment maneuver High frequency oscillatory ventilation compared with conventional in acute lung injury and acute respiratory distress syndrome. Respir mechanical ventilation in adult respiratory distress syndrome: a rand- Care. 2008;53(11):1441–9. omized controlled trial [ISRCTN24242669]. Crit Care. 2005;9(4):430–9. Grotberg et al. Critical Care (2023) 27:289 Page 13 of 15 76. Ferguson N, Cook D, Guyatt G, Mehta S, Hand L, Austin P, et al. High- 95. Soliman-Aboumarie H, Denault AY. How to assess systemic venous con- frequency oscillation in early acute respiratory distress syndrome. N gestion with point of care ultrasound. Eur Hear J Cardiovasc Imaging. Engl J Med. 2013;368(9):795–805. 2023;24(2):177–80. 77. Meade MO, Young D, Hanna S, Zhou Q, Bachman TE, Bollen C, et al. 96. De Backer D, Fagnoul D. Intensive care ultrasound: VI. Fluid responsive- Severity of hypoxemia and effect of high-frequency oscillatory ventila- ness and shock assessment. Ann Am Thorac Soc. 2014;11(1):129–36. tion in acute respiratory distress syndrome. Am J Respir Crit Care Med. 97. Boussuges A, Blanc P, Molenat F, Burnet H, Habib G, Sainty JM. Evalua- 2017;196(6):727–33. tion of left ventricular filling pressure by transthoracic Doppler echocar- 78. Fan E, Del Sorbo L, Goligher EC, Hodgson CL, Munshi L, Walkey AJ, et al. diography in the intensive care unit. Crit Care Med. 2002;30(2):362–7. An official American Thoracic Society/European Society of intensive 98. Lichtenstein DA, Mezière GA, Lagoueyte JF, Biderman P, Goldstein I, care medicine/society of critical care medicine clinical practice guide- Gepner A. A-lines and B-lines: lung ultrasound as a bedside tool for pre- line: Mechanical ventilation in adult patients with acute respiratory dicting pulmonary artery occlusion pressure in the critically ill. Chest. distress syndrome. Am J Respir Crit Care Med. 2017;195(9):1253–63. 2009;136(4):1014–20. 79. Parhar KKS, Zjadewicz K, Soo A, Sutton A, Zjadewicz M, Doig L, et al. 99. Repessé X, Charron C, Vieillard-Baron A. Intensive care ultrasound: V. Epidemiology, mechanical power, and 3-year outcomes in acute Goal-directed echocardiography. Ann Am Thorac Soc. 2014;11(1):122–8. respiratory distress syndrome patients using standardized screening: an 100. Vignon P, Repessé X, Begot E, Léger J, Jacob C, Bouferrache K, et al. observational cohort study. Ann Am Thorac Soc. 2019;16(10):1263–72. Comparison of echocardiographic indices used to predict fluid 80. Huhle R, Serpa Neto A, Schultz MJ, Gama de Abreu M. Is mechanical responsiveness in ventilated patients. Am J Respir Crit Care Med. power the final word on ventilator-induced lung injury?—no. Ann 2017;195(8):1022–32. Transl Med. 2018;6(19):394–394. 101. Meduri G, Golden E, Freire A, Taylor E, Zaman M, Carson S, et al. Meth- 81. Schaefer MS, Loring SH, Talmor D, Baedorf-Kassis EN. Comparison of ylprednisolone infusion in early severe ARDS: results of a randomized mechanical power estimations in mechanically ventilated patients with controlled trial. Chest. 2007;131(4):954–63. ARDS: a secondary data analysis from the EPVent study. Intensive Care 102. Steinberg K, Hudson L, Goodman R, Hough C, Lanken P, Hyzy R, et al. Med. 2021;47(1):130–2. Efficacy and safety of corticosteroids for persistent acute respiratory 82. Serpa Neto A, Deliberato RO, Johnson AEW, Bos LD, Amorim P, Pereira distress syndrome. N Engl J Med. 2006;354(16):1671–84. SM, et al. Mechanical power of ventilation is associated with mortality 103. Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, et al. in critically ill patients: an analysis of patients in two observational Dexamethasone treatment for the acute respiratory distress syndrome: cohorts. Intensive Care Med. 2018;44(11):1914–22. a multicentre, randomised controlled trial. Lancet Respir Med. 83. Costa ELV, Slutsky AS, Brochard LJ, Brower R, Serpa-Neto A, Cavalcanti 2020;8(3):267–76. AB, et al. Ventilatory variables and mechanical power in patients 104. Horby P, Lim WS, Emberson J, Mafham M, Bell J, Linsell L, et al. Dexa- with acute respiratory distress syndrome. Am J Respir Crit Care Med. methasone in hospitalized patients with Covid-19. N Engl J Med. 2021;204(3):303–11. 2021;384(8):693–704. 84. Guérin C, Albert RK, Beitler J, Gattinoni L, Jaber S, Marini JJ, et al. Prone 105. Sterne JAC, Murthy S, Diaz JV, Slutsky AS, Villar J, Angus DC, et al. position in ARDS patients: why, when, how and for whom. Intensive Association between administration of systemic corticosteroids and Care Med. 2020;46(12):2385–96. mortality among critically Ill patients with COVID-19: a meta-analysis. 85. Gattinoni L, Busana M, Giosa L, Macrì MM, Quintel M. Prone position- JAMA J Am Med Assoc. 2020;324(13):1330–41. ing in acute respiratory distress syndrome. Semin Respir Crit Care Med. 106. Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, 2019;40(1):94–100. et al. Effect of dexamethasone on days alive and ventilator-free in 86. Cortney Henderson A, Sá RC, Theilmann RJ, Buxton RB, Kim Prisk G, patients with moderate or severe acute respiratory distress syndrome Hopkins SR. The gravitational distribution of ventilation-perfusion ratio and COVID-19: the CoDEX randomized clinical trial. JAMA J Am Med is more uniform in prone than supine posture in the normal human Assoc. 2020;324(13):1307–16. lung. J Appl Physiol. 2013;115(3):313–24. 107. Sinha P, Furfaro D, Cummings MJ, Abrams D, Delucchi K, Maddali MV, 87. Scholten EL, Beitler JR, Prisk GK, Malhotra A. Treatment of ARDS with et al. Latent class analysis reveals COVID-19-related acute respiratory prone positioning. Chest. 2017;151(1):215–24. distress syndrome subgroups with differential responses to corticoster- 88. Katira BH, Osada K, Engelberts D, Bastia L, Damiani LF, Li X, et al. Positive oids. Am J Respir Crit Care Med. 2021;204(11):1274–85. end-expiratory pressure, pleural pressure, and regional compliance 108. Hurford WE. Neuromuscular blockade applicability in early acute during Pronation An Experimental Study. Am J Respir Crit Care Med. respiratory distress syndrome. Anesthesiology. 2020;6:1577–84. 2021;203(10):1266–74. 109. Papazian L, Forel J-M, Gacouin A, Penot-Ragon C, Perrin G, Loundou 89. Yoshida T, Engelberts D, Chen H, Li X, Katira B, Otulakowski G, et al. A, et al. Neuromuscular blockers in early acute respiratory distress Prone position minimizes the exacerbation of effort-dependent lung syndrome. N Engl J Med. 2011;365:687–96. injury: exploring the mehcanism in pigs and evaluating injury in rab- 110. Moss M, Huang D, Brower R, Ferguson N, Ginde A, Gong M, et al. Early bits. Anesthesiology. 2022;136(5):779–91. neuromuscular blockade in the acute respiratory distress syndrome. N 90. Munshi L, Del Sorbo L, Adhikari NKJ, Hodgson CL, Wunsch H, Meade Engl J Med. 2019;380(21):1997–2008. MO, et al. Prone position for acute respiratory distress syndrome: 111. Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, a systematic review and meta-analysis. Ann Am Thorac Soc. et al. Efficacy and safety of a paired sedation and ventilator weaning 2017;14(4):280–8. protocol for mechanically ventilated patients in intensive care (Awak- 91. Sud S, Friedrich JO, Adhikari NKJ, Taccone P, Mancebo J, Polli F, et al. ening and Breathing Controlled trial): a randomised controlled trial. Effect of prone positioning during mechanical ventilation on mortality Lancet. 2008;371(9607):126–34. among patients with acute respiratory distress syndrome: a systematic 112. Puthucheary Z, Rawal J, Ratnayake G, Harridge S, Montgomery H, Hart review and meta-analysis. C Can Med Assoc J. 2014;186(10):381–90. N. Neuromuscular blockade and skeletal muscle weakness in critically 92. Gattinoni L, Carlesso E, Taccone P, Polli F, Guérin C, Mancebo J. Prone ill patients: time to rethink the evidence? Am J Respir Crit Care Med. positioning improves survival in severe ARDS: a pathophysiologic 2012;185(9):911–7. review and individual patient meta-analysis. Minerva Anestesiol. 113. Herridge MS, Azoulay É. Outcomes after critical illness. N Engl J Med. 2010;76(6):448–54. 2023;388(10):913–24. 93. Albert R, Keniston A, Baboi L, Ayzac L, Guerin C. Prone position–induced 114. Bouju P, Tadié JM, Barbarot N, Letheulle J, Uhel F, Fillatre P, et al. Clinical improvement ingas exchange does not predict improvedsurvival in assessment and train-of-four measurements in critically ill patients the acute respiratorydistress syndrome. Am J Respir Crit Care Med. treated with recommended doses of cisatracurium or atracurium for 2014;189(4):494–6. neuromuscular blockade: a prospective descriptive study. Ann Inten- 94. Park J, Lee HY, Lee J, Lee SM. Effect of prone positioning on oxygenation sive Care. 2017;7(1):1–10. and static respiratory system compliance in COVID-19 ARDS vs non- 115. Bass BS, Vance ML, Reddy A, Bauer SR, Roach E, Torbic H, et al. Bispectral COVID ARDS. Respir Res. 2021;22(1):1–12. index for titrating sedation in ARDS patients during neuromuscular blockade. Am J Crit Care. 2019;28(5):377–84. Grotberg et al. Critical Care (2023) 27:289 Page 14 of 15 116. Afshari A, Brok J, Møller AM, Wetterslev J. Inhaled nitric oxide for acute oxygenation for acute respiratory distress syndrome: a retrospective respiratory distress syndrome and acute lung injury in adults and international multicenter study. Crit Care Med. 2015;43(3):654–64. children: a systematic review with meta-analysis and trial sequential 137. Serpa Neto A, Schmidt M, Azevedo LCP, Bein T, Brochard L, Beutel G, analysis. Anesth Analg. 2011;112(6):1411–21. et al. Associations between ventilator settings during extracorporeal 117. Fuller BM, Mohr NM, Skrupky L, Fowler S, Kollef MH, Carpenter CR. membrane oxygenation for refractory hypoxemia and outcome in The use of inhaled prostaglandins in patients with ARDS: a systematic patients with acute respiratory distress syndrome: a pooled individual review and meta-analysis. Chest. 2015;147(6):1510–22. patient data analysis: mechanical ventilation during ECMO. Intensive 118. Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for Care Med. 2016;42(11):1672–84. acute respiratory distress syndrome (ARDS) in children and adults. 138. Araos J, Alegria L, Garcia P, Cruces P, Soto D, Erranz B, et al. Near-apneic Cochrane Database Syst Rev. 2016;2016(6):1–98. ventilation decreases lung injury and fibroproliferation in an acute 119. Poonam PBH, Koscik R, Nguyen T, Rikhi S, Lin HM. Nitric oxide versus respiratory distress syndrome model with extracorporeal membrane epoprostenol for refractory hypoxemia in Covid-19. PLoS ONE. oxygenation. Am J Respir Crit Care Med. 2019;199(5):603–12. 2022;17(6):1–12. 139. Rozencwajg S, Guihot A, Franchineau G, Lescroat M, Bréchot N, 120. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for Hékimian G, et al. Ultra-protective ventilation reduces biotrauma ARDS in adults. N Engl J Med. 2011;365(20):1905–14. in patients on venovenous extracorporeal membrane oxygena- 121. Fan E, Gattinoni L, Combes A, Schmidt M, Peek G, Brodie D, et al. tion for severe acute respiratory distress syndrome. Crit Care Med. Venovenous extracorporeal membrane oxygenation for acute respira- 2019;47(11):1505–12. tory failure: A clinical review from an international group of experts. 140. Grasso S, Stripoli T, Mazzone P, Pezzuto M, Lacitignola L, Centonze P, Intensive Care Med. 2016;42(5):712–24. et al. Low respiratory rate plus minimally invasive extracorporeal ­Co2 122. Ventetuolo CE, Muratore CS. Extracorporeal life support in critically III removal decreases systemic and pulmonary inflammatory mediators adults. Am J Respir Crit Care Med. 2014;190(5):497–508. in experimental Acute Respiratory Distress Syndrome. Crit Care Med. 123. Abrams D, Brodie D. Extracorporeal membrane oxygenation for adult 2014;42(6):e451–60. respiratory failure: 2017 update. Chest. 2017;152(3):639–49. 141. Del Sorbo L, Goffi A, Tomlinson G, Pettenuzzo T, Facchin F, Vendramin 124. Peek GJ, Mugford M, Tiruvoipati R, Wilson A, Allen E, Thalanany MM, A, et al. Effect of driving pressure change during extracorporeal et al. Efficacy and economic assessment of conventional ventilatory membrane oxygenation in adults with acute respiratory distress support versus extracorporeal membrane oxygenation for severe adult syndrome: a randomized crossover physiologic study. Crit Care Med. respiratory failure (CESAR): a multicentre randomised controlled trial. 2020;48(12):1771–8. Lancet. 2009;374(9698):1351–63. 142. Guérin C. Individualization of positive end-expiratory pressure setting in 125. Combes A, Hajage D, Capellier G, Demoule A, Lavoué S, Guervilly C, patients with acute respiratory distress syndrome under extracorporeal et al. Extracorporeal membrane oxygenation for severe acute respira- membrane oxygenation: inputs from electrical impedance tomogra- tory distress syndrome. N Engl J Med. 2018;378(21):1965–75. phy. Am J Respir Crit Care Med. 2017;196(4):404–5. 126. Munshi L, Walkey A, Goligher E, Pham T, Uleryk EM, Fan E. Venovenous 143. Soulé C, Crognier L, Puel F, Ruiz S, Seguin T, Fourcade O, et al. Assess- extracorporeal membrane oxygenation for acute respiratory distress ment of electrical impedance tomography to set optimal positive syndrome: a systematic review and meta-analysis. Lancet Respir Med. end-expiratory pressure for venoarterial extracorporeal membrane 2019;7(2):163–72. oxygenation-treated patients. Crit Care Med. 2021;49(6):923–33. 127. Goligher EC, Tomlinson G, Hajage D, Wijeysundera DN, Fan E, Jüni P, 144. Puel F, Crognier L, Soulé C, Vardon-Bounes F, Ruiz S, Seguin T, et al. et al. Extracorporeal membrane oxygenation for severe acute respira- Assessment of electrical impedance tomography to set optimal posi- tory distress syndrome and posterior probability of mortality benefit in tive end-expiratory pressure for veno-venous ECMO-treated severe a post hoc Bayesian analysis of a randomized clinical trial. JAMA J Am ARDS patients. J Crit Care. 2020;2020(60):38–44. Med Assoc. 2018;320(21):2251–9. 145. Mekontso Dessap A, Boissier F, Charron C, Bégot E, Repessé X, Legras A, 128. Schmidt M, Pham T, Arcadipane A, Agerstrand C, Ohshimo S, Pellegrino et al. Acute cor pulmonale during protective ventilation for acute res- V, et al. Mechanical ventilation management during extracorporeal piratory distress syndrome: prevalence, predictors, and clinical impact. membrane oxygenation for acute respiratory distress syndrome an Intensive Care Med. 2016;42(5):862–70. international multicenter prospective cohort. Am J Respir Crit Care 146. Cavaleiro P, Masi P, Bagate F, D’Humières T, Mekontso DA. Acute cor Med. 2019;200(8):1002–12. pulmonale in Covid-19 related acute respiratory distress syndrome. Crit 129. Belliato M, Epis F, Cremascoli L, Ferrari F, Quattrone MG, Fisser C, et al. Care. 2021;25(1):1–3. Mechanical power during veno-venous extracorporeal membrane oxy- 147. Canada E, Benumof J, Tousdale F. Pulmonary vascular resistance cor- genation initiation: a pilot-study. Membranes (Basel). 2021;11(1):1–11. relates in intact normal and abnormal canine lungs. Crit Care Med. 130. Chiu LC, Lin SW, Chuang LP, Li HH, Liu PH, Tsai FC, et al. Mechanical 1982;10(11):719–23. power during extracorporeal membrane oxygenation and hospital 148. Jardin F, Vieillard-Baron A. Right ventricular function and positive mortality in patients with acute respiratory distress syndrome. Crit Care. pressure ventilation in clinical practice: from hemodynamic subsets to 2021;25(1):1–11. respirator settings. Intensive Care Med. 2003;29(9):1426–34. 131. Marhong JD, Munshi L, Detsky M, Telesnicki T, Fan E. Mechanical ventila- 149. Smith NJ, Park S, Zundel MT, Dong H, Szabo A, Cain MT, et al. Extracor- tion during extracorporeal life support (ECLS): a systematic review. poreal membrane oxygenation for COVID-19: an evolving experience Intensive Care Med. 2015;41(6):994–1003. through multiple waves. Artif Organs. 2022;46(11):2257–65. 132. Assouline B, Combes A, Schmidt M. Setting and monitoring of mechan- 150. Tatooles AJ, Mustafa AK, Joshi DJ, Pappas PS. Extracorporeal mem- ical ventilation during venovenous ECMO. Crit care. 2023;27(1):95. brane oxygenation with right ventricular support in COVID-19 133. Marhong JD, Telesnicki T, Munshi L, Del Sorbo L, Detsky M, Fan E. patients with severe acute respiratory distress syndrome. JTCVS Open. Mechanical ventilation during extracorporeal membrane oxygenation 2021;8(December):90–6. an international survey. Ann Am Thorac Soc. 2014;11(6):939–44. 151. Herridge M, Cheung A, Tansey C, Matte-Martyn A, Diaz-Granados N, 134. Kodali BS, Urman RD. Capnography during cardiopulmonary resuscita- Al-Saidi F, et al. One-year outcomes in survivors of the acute respiratory tion: Current evidence and future directions. J Emergencies Trauma distress syndrome. N Engl J Med. 2003;348(8):683–93. Shock. 2014;7(4):332–40. 152. Rossong H, Debreuil S, Yan W, Hiebert BM, Singal RK, Arora RC, et al. 135. Magunia H, Haeberle HA, Henn P, Mehrländer M, Vlatten PO, Mirakaj V, Long-term survival and quality of life after extracorporeal membrane et al. Early driving pressure changes predict outcomes during veno- oxygenation. J Thorac Cardiovasc Surg. 2022. https://​doi.​org/​10.​1016/j.​ venous extracorporeal membrane oxygenation for acute respiratory jtcvs.​2021.​10.​077. distress syndrome. Crit Care Res Pract. 2020. https://​doi.​org/​10.​1155/​ 153. Puthucheary ZA, Rawal J, McPhail M, Connolly B, Ratnayake G, 2020/​69581​52. Chan P, et al. Acute skeletal muscle wasting in critical illness. JAMA. 136. Schmidt M, Stewart C, Bailey M, Nieszkowska A, Kelly J, Murphy L, et al. 2013;310(15):1591–600. Mechanical ventilation management during extracorporeal membrane 154. Pfoh ER, Wozniak AW, Colantuoni E, Dinglas VD, Mendez-Tellez PA, Shanholtz C, et al. Physical declines occurring after hospital discharge Grotberg et al. Critical Care (2023) 27:289 Page 15 of 15 in ARDS survivors: a 5-year longitudinal study. Intensive Care Med. 2016;42(10):1557–66. 155. Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, et al. The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med. 2012;185(12):1307–15. 156. Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larson-Lohr V. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. Am J Respir Crit Care Med. 1999;160(1):50–6. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. 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