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Background: Efficacy of inhaled therapy such as Nitric Oxide (iNO) during mechanical ventilation may depend on airway patency. We hypothesized that airway closure and lung collapse, countered by positive end-expiratory pressure (PEEP), influence iNO efficacy. This could support the role of an adequate PEEP titration for inhalation therapy. The main aim of this study was to assess the effect of iNO with PEEP set above or below the airway opening pressure (AOP) generated by airway closure, on hemodynamics and gas exchange in swine models of acute respiratory distress syndrome. Fourteen pigs randomly underwent either bilateral or asymmetrical two-hit model of lung injury. Airway closure and lung collapse were measured with electrical impedance tomography as well as ventilation/perfusion ratio (V/Q). After AOP detection, the effect of iNO (10ppm) was studied with PEEP set randomly above or below regional AOP. Respiratory mechanics, hemodynamics, and gas-exchange were recorded., Results: All pigs presented airway closure (AOP > 0.5cmH 2 O) after injury. In bilateral injury, iNO was associated with an improved mean pulmonary pressure from 49 ± 8 to 42 ± 7mmHg; (p = 0.003), and ventilation/perfusion matching, caused by a reduction in pixels with low V/Q and shunt from 16%[IQR:13-19] to 9%[IQR:4-12] (p = 0.03) only at PEEP set above AOP. iNO had no effect on hemodynamics or gas exchange for PEEP below AOP (low V/Q 25%[IQR:16-30] to 23%[IQR:14-27]; p = 0.68). In asymmetrical injury, iNO improved pulmonary hemodynamics and ventilation/perfusion matching independently from the PEEP set. iNO was associated with improved oxygenation in all cases., Conclusions: In an animal model of bilateral lung injury, PEEP level relative to AOP markedly influences iNO efficacy on pulmonary hemodynamics and ventilation/perfusion match, independently of oxygenation., (© 2024. The Author(s).)

Background: Reverse triggering (RT) was described in 2013 as a form of patient-ventilator asynchrony, where patient's respiratory effort follows mechanical insufflation. Diagnosis requires esophageal pressure (P es ) or diaphragmatic electrical activity (EA di ), but RT can also be diagnosed using standard ventilator waveforms., Hypothesis: We wondered (1) how frequently RT would be present but undetected in the figures from literature, especially before 2013; (2) whether it would be more prevalent in the era of small tidal volumes after 2000., Methods: We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, from 1950 to 2017, with key words related to asynchrony to identify papers with figures including ventilator waveforms expected to display RT if present. Experts labelled waveforms. 'Definite' RT was identified when P es or EA di were in the tracing, and 'possible' RT when only flow and pressure waveforms were present. Expert assessment was compared to the author's descriptions of waveforms., Results: We found 65 appropriate papers published from 1977 to now, containing 181 ventilator waveforms. 21 cases of 'possible' RT and 25 cases of 'definite' RT were identified by the experts. 18.8% of waveforms prior to 2013 had evidence of RT. Most cases were published after 2000 (1 before vs. 45 after, p = 0.03). 54% of RT cases were attributed to different phenomena. A few cases of identified RT were already described prior to 2013 using different terminology (earliest in 1997). While RT cases attributed to different phenomena decreased after 2013, 60% of 'possible' RT remained missed., Conclusion: RT has been present in the literature as early as 1997, but most cases were found after the introduction of low tidal volume ventilation in 2000. Following 2013, the number of undetected cases decreased, but RT are still commonly missed. Reverse Triggering, A Missed Phenomenon in the Literature. Critical Care Canada Forum 2019 Abstracts. Can J Anesth/J Can Anesth 67 (Suppl 1), 1-162 (2020). https://doi-org.myaccess.library.utoronto.ca/ https://doi.org/10.1007/s12630-019-01552-z ., (© 2024. The Author(s).)

Background: Pre-clinical studies suggest that dyssynchronous diaphragm contractions during mechanical ventilation may cause acute diaphragm dysfunction. We aimed to describe the variability in diaphragm contractile loading conditions during mechanical ventilation and to establish whether dyssynchronous diaphragm contractions are associated with the development of impaired diaphragm dysfunction., Methods: In patients receiving invasive mechanical ventilation for pneumonia, septic shock, acute respiratory distress syndrome, or acute brain injury, airway flow and pressure and diaphragm electrical activity (Edi) were recorded hourly around the clock for up to 7 days. Dyssynchronous post-inspiratory diaphragm loading was defined based on the duration of neural inspiration after expiratory cycling of the ventilator. Diaphragm function was assessed on a daily basis by neuromuscular coupling (NMC, the ratio of transdiaphragmatic pressure to diaphragm electrical activity)., Results: A total of 4508 hourly recordings were collected in 45 patients. Edi was low or absent (≤ 5 µV) in 51% of study hours (median 71 h per patient, interquartile range 39-101 h). Dyssynchronous post-inspiratory loading was present in 13% of study hours (median 7 h per patient, interquartile range 2-22 h). The probability of dyssynchronous post-inspiratory loading was increased with reverse triggering (odds ratio 15, 95% CI 8-35) and premature cycling (odds ratio 8, 95% CI 6-10). The duration and magnitude of dyssynchronous post-inspiratory loading were associated with a progressive decline in diaphragm NMC (p < 0.01 for interaction with time)., Conclusions: Dyssynchronous diaphragm contractions may impair diaphragm function during mechanical ventilation., Trial Registration: MYOTRAUMA, ClinicalTrials.gov NCT03108118. Registered 04 April 2017 (retrospectively registered)., (© 2024. The Author(s).)

Background: Aerosol barrier enclosure systems have been designed to prevent airborne contamination, but their safety has been questioned. A vacuum tent was designed with active continuous suctioning to minimize risks of aerosol dispersion. We tested its efficacy, risk of rebreathing, and usability on a bench, in healthy volunteers, and in an ergonomic clinical assessment study., Methods: First, a manikin with airway connected to a breathing simulator was placed inside the vacuum tent to generate active breathing, cough, and CO 2 production; high-flow nasal cannula (HFNC) was applied in the manikin's nares. Negative pressure was applied in the vacuum tent's apex port using wall suction. Fluorescent microparticles were aerosolized in the vacuum tent for qualitative assessment. To quantify particles inside and around vacuum tent (aerosol retention), an airtight aerosol chamber with aerosolized latex microparticles was used. The vacuum tent was tested on healthy volunteers breathing with and without HFNC. Last, its usability was assessed in 5 subjects by 5 different anesthesiologists for delivery of full anesthesia, including intubation and extubation., Results: The vacuum tent was adjusted until no leak was visualized using fluorescent particles. The efficacy in retaining microparticles was confirmed quantitatively. CO 2 accumulation inside the vacuum tent showed an inverse correlation with the suction flow in all conditions (normal breathing and HFNC 30 or 60 L/min) in bench and healthy volunteers. Particle removal efficacy and safe breathing conditions (CO 2 , temperature) were reached when suctioning was at least 60 L/min or 20 L/min > HFNC flow. Five subjects were successfully intubated and anesthetized without ergonomic difficulties and with minimal interference with workflow and an excellent overall assessment by the anesthesiologists., Conclusions: The vacuum tent effectively minimized aerosol dispersion. Its continuous suction system set at a high suction flow was crucial to avoid the spread of aerosol particles and CO 2 rebreathing., Competing Interests: Dr Rezende-Neto invented the vacuum tent and is the cofounder of InventoRR MD. Dr Brochard’s laboratory discloses relationships with STIMIT, Medtronic, Dräger, Sentec, Philips, and Fisher & Paykel. The remaining authors have disclosed no conflicts of interest., (Copyright © 2024 by Daedalus Enterprises.)

Background: Lung- and diaphragm-protective (LDP) ventilation may prevent diaphragm atrophy and patient self-inflicted lung injury in acute respiratory failure, but feasibility is uncertain. The objectives of this study were to estimate the proportion of patients achieving LDP targets in different modes of ventilation, and to identify predictors of need for extracorporeal carbon dioxide removal (ECCO 2 R) to achieve LDP targets., Methods: An in silico clinical trial was conducted using a previously published mathematical model of patient-ventilator interaction in a simulated patient population (n = 5000) with clinically relevant physiological characteristics. Ventilation and sedation were titrated according to a pre-defined algorithm in pressure support ventilation (PSV) and proportional assist ventilation (PAV+) modes, with or without adjunctive ECCO 2 R, and using ECCO 2 R alone (without ventilation or sedation). Random forest modelling was employed to identify patient-level factors associated with achieving targets., Results: After titration, the proportion of patients achieving targets was lower in PAV+ vs. PSV (37% vs. 43%, odds ratio 0.78, 95% CI 0.73-0.85). Adjunctive ECCO 2 R substantially increased the probability of achieving targets in both PSV and PAV+ (85% vs. 84%). ECCO 2 R alone without ventilation or sedation achieved LDP targets in 9%. The main determinants of success without ECCO 2 R were lung compliance, ventilatory ratio, and strong ion difference. In silico trial results corresponded closely with the results obtained in a clinical trial of the LDP titration algorithm (n = 30)., Conclusions: In this in silico trial, many patients required ECCO 2 R in combination with mechanical ventilation and sedation to achieve LDP targets. ECCO 2 R increased the probability of achieving LDP targets in patients with intermediate degrees of derangement in elastance and ventilatory ratio., (© 2024. The Author(s).)

Background: Internal redistribution of gas, referred to as pendelluft, is a new potential mechanism of effort-dependent lung injury. Neurally-adjusted ventilatory assist (NAVA) and proportional assist ventilation (PAV +) follow the patient's respiratory effort and improve synchrony compared with pressure support ventilation (PSV). Whether these modes could prevent the development of pendelluft compared with PSV is unknown. We aimed to compare pendelluft magnitude during PAV + and NAVA versus PSV in patients with resolving acute respiratory distress syndrome (ARDS)., Methods: Patients received either NAVA, PAV + , or PSV in a crossover trial for 20-min using comparable assistance levels after controlled ventilation (> 72 h). We assessed pendelluft (the percentage of lost volume from the non-dependent lung region displaced to the dependent region during inspiration), drive (as the delta esophageal swing of the first 100 ms [ΔP es 100 ms ]) and inspiratory effort (as the esophageal pressure-time product per minute [PTP min ]). We performed repeated measures analysis with post-hoc tests and mixed-effects models., Results: Twenty patients mechanically ventilated for 9 [5-14] days were monitored. Despite matching for a similar tidal volume, respiratory drive and inspiratory effort were slightly higher with NAVA and PAV + compared with PSV (ΔP es 100 ms of -2.8 [-3.8--1.9] cm H 2 O, -3.6 [-3.9--2.4] cm H 2 O and -2.1 [-2.5--1.1] cm H 2 O, respectively, p < 0.001 for both comparisons; PTP min of 155 [118-209] cm H 2 O s/min, 197 [145-269] cm H 2 O s/min, and 134 [93-169] cm H 2 O s/min, respectively, p < 0.001 for both comparisons). Pendelluft magnitude was higher in NAVA (12 ± 7%) and PAV + (13 ± 7%) compared with PSV (8 ± 6%), p < 0.001. Pendelluft magnitude was strongly associated with respiratory drive (β = -2.771, p-value < 0.001) and inspiratory effort (β = 0.026, p  < 0.001), independent of the ventilatory mode. A higher magnitude of pendelluft in proportional modes compared with PSV existed after adjusting for PTP min (β = 2.606, p = 0.010 for NAVA, and β = 3.360, p = 0.004 for PAV +), and only for PAV + when adjusted for respiratory drive (β = 2.643, p = 0.009 for PAV +)., Conclusions: Pendelluft magnitude is associated with respiratory drive and inspiratory effort. Proportional modes do not prevent its occurrence in resolving ARDS compared with PSV., (© 2023. The Author(s).)

Background: The Oxylator is an automatic resuscitator, powered only by an oxygen cylinder with no electricity required, that could be used in acute respiratory failure in situations in which standard mechanical ventilation is not available or feasible. We aimed to assess the feasibility and safety of mechanical ventilation by using this automatic resuscitator in an animal model of ARDS., Methods: A randomized experimental study in a porcine ARDS model with 12 pigs randomized to the Oxylator group or the control group (6 per group) and ventilated for 4 h. In the Oxylator group, peak pressure was set at 20 cm H 2 O and PEEP was set at the lowest observed breathing frequency during a decremental PEEP titration. The control pigs were ventilated with a conventional ventilator by using protective settings and PEEP at the crossing point of collapse and overdistention, as indicated by electrical impedance tomography. Our end points were feasibility and safety as well as respiratory mechanics, gas exchange, and hemodynamics., Results: After lung injury, the mean ± SD respiratory system compliance and P aO 2 /F IO 2 were 13 ± 2 mL/cm H 2 O and 61 ± 17 mm Hg, respectively. The mean ± SD total PEEP was 10 ± 2 cm H 2 O and 13 ± 2 cm H 2 O in the control and Oxylator groups, respectively ( P = .046). The mean plateau pressure was kept to < 30 cm H 2 O in both groups. In the Oxylator group, the tidal volume was transiently > 8 mL/kg but was 6 ± 0.4 mL/kg at 4 h, whereas the breathing frequency increased from 38 ± 4 to 48 ± 3 breaths/min ( P < .001). There was no difference in driving pressure, compliance, P aO 2 /F IO 2 , and pulmonary shunt between the groups. The mean ± SD P aCO 2 was higher in the Oxylator group after 4 h, 74 ± 9 mm Hg versus 58 ± 6 mm Hg ( P < .001). There were no differences in hemodynamics between the groups, including blood pressure and cardiac output., Conclusions: Short-term mechanical ventilation by using an automatic resuscitator and a fixed pressure setting in an ARDS animal model was feasible and safe., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Background: Insufficient or excessive respiratory effort during acute hypoxemic respiratory failure (AHRF) increases the risk of lung and diaphragm injury. We sought to establish whether respiratory effort can be optimized to achieve lung- and diaphragm-protective (LDP) targets (esophageal pressure swing - 3 to - 8 cm H 2 O; dynamic transpulmonary driving pressure ≤ 15 cm H 2 O) during AHRF., Methods: In patients with early AHRF, spontaneous breathing was initiated as soon as passive ventilation was not deemed mandatory. Inspiratory pressure, sedation, positive end-expiratory pressure (PEEP), and sweep gas flow (in patients receiving veno-venous extracorporeal membrane oxygenation (VV-ECMO)) were systematically titrated to achieve LDP targets. Additionally, partial neuromuscular blockade (pNMBA) was administered in patients with refractory excessive respiratory effort., Results: Of 30 patients enrolled, most had severe AHRF; 16 required VV-ECMO. Respiratory effort was absent in all at enrolment. After initiating spontaneous breathing, most exhibited high respiratory effort and only 6/30 met LDP targets. After titrating ventilation, sedation, and sweep gas flow, LDP targets were achieved in 20/30. LDP targets were more likely to be achieved in patients on VV-ECMO (median OR 10, 95% CrI 2, 81) and at the PEEP level associated with improved dynamic compliance (median OR 33, 95% CrI 5, 898). Administration of pNMBA to patients with refractory excessive effort was well-tolerated and effectively achieved LDP targets., Conclusion: Respiratory effort is frequently absent  under deep sedation but becomes excessive when spontaneous breathing is permitted in patients with moderate or severe AHRF. Systematically titrating ventilation and sedation can optimize respiratory effort for lung and diaphragm protection in most patients. VV-ECMO can greatly facilitate the delivery of a LDP strategy., Trial Registration: This trial was registered in Clinicaltrials.gov in August 2018 (NCT03612583)., (© 2022. The Author(s).)

High-flow nasal cannula (HFNC) is extensively used for acute respiratory failure. However, questions remain regarding its physiological effects. We explored 1) whether HFNC produced similar effects to continuous positive airway pressure (CPAP); 2) possible explanations of respiratory rate changes; 3) the effects of mouth opening. Two studies were conducted: a bench study using a manikin's head with lungs connected to a breathing simulator while delivering HFNC flow rates from 0 to 60L/min; a physiological cross-over study in 10 healthy volunteers receiving HFNC (20 to 60L/min) with the mouth open or closed and CPAP 4cmH 2 O delivered through face-mask. Nasopharyngeal and esophageal pressures were measured; tidal volume and flow were estimated using calibrated electrical impedance tomography. In the bench study, nasopharyngeal pressure at end-expiration reached 4cmH 2 O with HFNC at 60L/min, while tidal volume decreased with increasing flow. In volunteers with HFNC at 60L/min, nasopharyngeal pressure reached 6.8cmH 2 O with mouth closed and 0.8cmH 2 O with mouth open; p<0.001. When increasing HFNC flow, respiratory rate decreased by lengthening expiratory time, tidal volume did not change, and effort decreased (pressure-time product of the respiratory muscles); at 40L/min, effort was equivalent between CPAP and HFNC40L/min and became lower at 60L/min (p=0.045). During HFNC with mouth closed, and not during CPAP, resistance to breathing was increased, mostly during expiration. In conclusion, mouth closure during HFNC induces a positive nasopharyngeal pressure proportional to flow rate and an increase in expiratory resistance that might explain the prolonged expiration and reduction in respiratory rate and effort, and contribute to physiological benefits.

Background: Our purpose was to summarise the prognostic associations between various clinical risk factors and development of acute respiratory distress syndrome (ARDS) following traumatic injury., Methods: We conducted this review in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and CHARMS (Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modeling Studies) guidelines. We searched six databases from inception through December 2020. We included English language studies describing the clinical risk factors associated with development of post-traumatic ARDS, as defined by either the American-European Consensus Conference or Berlin definition. We pooled adjusted odds ratios for prognostic factors using the random effects method. We assessed risk of bias using the QUIPS (Quality in Prognosis Studies) tool and certainty of findings using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology., Results: We included 39 studies involving 5 350 927 patients. We identified the amount of crystalloid resuscitation as a potentially modifiable prognostic factor associated with development of post-traumatic ARDS (adjusted OR 1.19, 95% CI 1.15-1.24 for each additional litre of crystalloid administered within the first 6 h after injury; high certainty). Non-modifiable prognostic factors with a moderate or high certainty of association with post-traumatic ARDS included increasing age, non-Hispanic White race, blunt mechanism of injury, presence of head injury, pulmonary contusion or rib fracture and increasing chest injury severity., Conclusions: We identified one important modifiable factor, the amount of crystalloid resuscitation within the first 24 h of injury, and several non-modifiable factors associated with development of post-traumatic ARDS. This information should support the judicious use of crystalloid resuscitation in trauma patients and may inform development of risk stratification tools., Competing Interests: Conflict of interest: A. Tran has nothing to disclose. Conflict of interest: S.M. Fernando has nothing to disclose. Conflict of interest: L.J. Brochard has nothing to disclose. Conflict of interest: E. Fan reports receiving personal fees from ALung Technologies, Baxter, Fresenius Medical Care, Getinge and MC3 Cardiopulmonary, outside of the submitted work. Conflict of interest: K. Inaba has nothing to disclose. Conflict of interest: N.D. Ferguson has nothing to disclose. Conflict of interest. C. Calfee receives grant funding from the NIH (related) as well as Roche-Genentech and Quantum Leap Healthcare Collaborative, outside of the submitted work; she has served as a medical advisor to Roche-Genentech, Bayer, CSL Behring, Quark Pharmaceuticals, Vasomune and Gen1e Life Sciences, outside of the submitted work. Conflict of interest: C.S. Calfee has nothing to disclose. K.E.A. Burns is supported by a Physician Services Incorporated-50 Mid-Career Clinical Research Award. Conflict of interest: D. Brodie reports receiving research support from ALung Technologies, outside of the submitted work, and was previously on their medical advisory board; he has been on the medical advisory boards for Baxter, Abiomed, Xenios AG and Hemovent. Conflict of interest: V.A. McCredie has nothing to disclose. Conflict of interest: D.Y. Kim has nothing to disclose. Conflict of interest: K. Kyeremanteng has nothing to disclose. Conflict of interest: J. Lampron has nothing to disclose. Conflict of interest: A.S. Slutsky reports consulting for Baxter and Xenios AG. Conflict of interest: A. Combes reports receiving personal fees from Maquet, Xenios AG and Baxter International Inc., outside of the submitted work. Conflict of interest: B. Rochwerg is supported by a Hamilton Health Sciences New Investigator Grant., (Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: External chest-wall compression (ECC) is sometimes used in ARDS patients despite lack of evidence. It is currently unknown whether this practice has any clinical benefit in patients with COVID-19 ARDS (C-ARDS) characterized by a respiratory system compliance (C rs ) < 35 mL/cmH 2 O., Objectives: To test if an ECC with a 5 L-bag in low-compliance C-ARDS can lead to a reduction in driving pressure (DP) and improve gas exchange, and to understand the underlying mechanisms., Methods: Eleven patients with low-compliance C-ARDS were enrolled and underwent 4 steps: baseline, ECC for 60 min, ECC discontinuation and PEEP reduction. Respiratory mechanics, gas exchange, hemodynamics and electrical impedance tomography were recorded. Four pigs with acute ARDS were studied with ECC to understand the effect of ECC on pleural pressure gradient using pleural pressure transducers in both non-dependent and dependent lung regions., Results: Five minutes of ECC reduced DP from baseline 14.2 ± 1.3 to 12.3 ± 1.3 cmH 2 O (P < 0.001), explained by an improved lung compliance. Changes in DP by ECC were strongly correlated with changes in DP obtained with PEEP reduction (R 2  = 0.82, P < 0.001). The initial benefit of ECC decreased over time (DP = 13.3 ± 1.5 cmH 2 O at 60 min, P = 0.03 vs. baseline). Gas exchange and hemodynamics were unaffected by ECC. In four pigs with lung injury, ECC led to a decrease in the pleural pressure gradient at end-inspiration [2.2 (1.1-3) vs. 3.0 (2.2-4.1) cmH 2 O, P = 0.035]., Conclusions: In C-ARDS patients with C rs  < 35 mL/cmH 2 O, ECC acutely reduces DP. ECC does not improve oxygenation but it can be used as a simple tool to detect hyperinflation as it improves C rs and reduces P pl gradient. ECC benefits seem to partially fade over time. ECC produces similar changes compared to PEEP reduction., (© 2022. The Author(s).)

Background: An abrupt lung deflation in rodents results in lung injury through vascular mechanisms. Ventilator disconnections during endo-tracheal suctioning in humans often cause cardio-respiratory instability. Whether repeated disconnections or lung deflations cause lung injury or oedema is not known and was tested here in a porcine large animal model., Methods: Yorkshire pigs (~ 12 weeks) were studied in three series. First, we compared PEEP abruptly deflated from 26 cmH 2 O or from PEEP 5 cmH 2 O to zero. Second, pigs were randomly crossed over to receive rapid versus gradual PEEP removal from 20 cmH 2 O. Third, pigs with relative volume overload, were ventilated with PEEP 15 cmH 2 O and randomized to repeated ETT disconnections (15 s every 15 min) or no disconnection for 3 h. Hemodynamics, pulmonary variables were monitored, and lung histology and bronchoalveolar lavage studied., Results: As compared to PEEP 5 cmH 2 O, abrupt deflation from PEEP 26 cmH 2 O increased PVR, lowered oxygenation, and increased lung wet-to-dry ratio. From PEEP 20 cmH 2 O, gradual versus abrupt deflation mitigated the changes in oxygenation and vascular resistance. From PEEP 15, repeated disconnections in presence of fluid loading led to reduced compliance, lower oxygenation, higher pulmonary artery pressure, higher lung wet-to-dry ratio, higher lung injury score and increased oedema on morphometry, compared to no disconnects., Conclusion: Single abrupt deflation from high PEEP, and repeated short deflations from moderate PEEP cause pulmonary oedema, impaired oxygenation, and increased PVR, in this large animal model, thus replicating our previous finding from rodents. Rapid deflation may thus be a clinically relevant cause of impaired lung function, which may be attenuated by gradual pressure release., (© 2022. The Author(s).)

Background: Prolonged need for mechanical ventilation greatly impacts life expectancy of patients after spinal cord injury (SCI). Weaning outcomes have never been systematically assessed. In this systematic review and meta-analysis, we aimed to investigate the probability of weaning success, duration of mechanical ventilation, mortality, and their predictors in mechanically ventilated patients with SCI., Methods: We searched six databases from inception until August 2021 for randomized-controlled trials and observational studies enrolling adult patients (≥ 16 years) with SCI from any cause requiring mechanical ventilation. Titles and abstracts were screened independently by two reviewers. Full texts of the identified articles were then assessed for eligibility. Data were extracted independently and in duplicate by pairs of authors, using a standardized data collection form. Synthetic results are reported as meta-analytic means and proportions, based on random effects models., Results: Thirty-nine studies (14,637 patients, mean age 43) were selected. Cervical lesions were predominant (12,717 patients had cervical lesions only, 1843 in association with other levels' lesions). Twenty-five studies were conducted in intensive care units (ICUs), 14 in rehabilitative settings. In ICU, the mean time from injury to hospitalization was 8 h [95% CI 7-9], mean duration of mechanical ventilation 27 days [20-34], probability of weaning success 63% [45-78] and mortality 8% [5-11]. Patients hospitalized in rehabilitation centres had a greater number of high-level lesions (C3 or above), were at 40 days [29-51] from injury and were ventilated for a mean of 97 days [65-128]; 82% [70-90] of them were successfully weaned, while mortality was 1% [0-19]., Conclusions: Although our study highlights the lack of uniform definition of weaning success, of clear factors associated with weaning outcomes, and of high-level evidence to guide optimal weaning in patients with SCI, it shows that around two-thirds of mechanically ventilated patients can be weaned in ICU after SCI. A substantial gain in weaning success can be obtained during rehabilitation, with additional duration of stay but minimal increase in mortality. The study is registered with PROSPERO (CRD42020156788)., (© 2021. The Author(s).)

Background: Current incidence and outcome of patients with acute hypoxaemic respiratory failure requiring mechanical ventilation in the intensive care unit (ICU) are unknown, especially for patients not meeting criteria for acute respiratory distress syndrome (ARDS)., Methods: An international, multicentre, prospective cohort study of patients presenting with hypoxaemia early in the course of mechanical ventilation, conducted during four consecutive weeks in the winter of 2014 in 459 ICUs from 50 countries (LUNG SAFE). Patients were enrolled with arterial oxygen tension/inspiratory oxygen fraction ratio ≤300 mmHg, new pulmonary infiltrates and need for mechanical ventilation with a positive end-expiratory pressure of ≥5 cmH 2 O. ICU prevalence, causes of hypoxaemia, hospital survival and factors associated with hospital mortality were measured. Patients with unilateral versus bilateral opacities were compared., Findings: 12 906 critically ill patients received mechanical ventilation and 34.9% with hypoxaemia and new infiltrates were enrolled, separated into ARDS (69.0%), unilateral infiltrate (22.7%) and congestive heart failure (CHF; 8.2%). The global hospital mortality was 38.6%. CHF patients had a mortality comparable to ARDS (44.1% versus 40.4%). Patients with unilateral-infiltrate had lower unadjusted mortality, but similar adjusted mortality compared to those with ARDS. The number of quadrants on chest imaging was associated with an increased risk of death. There was no difference in mortality comparing patients with unilateral-infiltrate and ARDS with only two quadrants involved., Interpretation: More than one-third of patients receiving mechanical ventilation have hypoxaemia and new infiltrates with a hospital mortality of 38.6%. Survival is dependent on the degree of pulmonary involvement whether or not ARDS criteria are reached., Competing Interests: Conflict of interest: T. Pham has nothing to disclose. Conflict of interest: A. Pesenti reports personal fees from Maquet, Novalung/Xenios, Baxter, Gilead and Boehringer Ingelheim, outside the submitted work. Conflict of interest: G. Bellani reports grants and personal fees from Draeger Medical, personal fees from Getinge, Hamilton, GE Healthcare, Dimar SRL, Intersurgical and Flowmeter SPA, outside the submitted work. Conflict of interest: G. Rubenfeld has nothing to disclose. Conflict of interest: E. Fan reports personal fees from ALung Technologies, Getinge and MC3 Cardiopulmonary, grants, personal fees and non-financial support from Fresenius Medical Care, outside the submitted work. Conflict of interest: G. Bugedo has nothing to disclose. Conflict of interest: J.A. Lorente has nothing to disclose. Conflict of interest: A.D.V. Fernandes has nothing to disclose. Conflict of interest: F. Van Haren has nothing to disclose. Conflict of interest: A. Bruhn has nothing to disclose. Conflict of interest: F. Rios has nothing to disclose. Conflict of interest: A. Esteban has nothing to disclose. Conflict of interest: L. Gattinoni has nothing to disclose. Conflict of interest: A. Larsson reports grants from the Swedish Heart and Lung Foundation, during the conduct of the study. Conflict of interest: D.F. McAuley reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim and Bayer, outside the submitted work; in addition, his institution has received funds from grants from the UK NIHR, Wellcome Trust, Innovate UK, NI HSC R&D Division, NI Chest Heart and Stroke, and MRC; is one of four named inventors on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution, The Queen's University of Belfast (http://www.google.com/patents/US8962032); and is a Director of Research for the Intensive Care Society and NIHR EME Programme Director. Conflict of interest: M. Ranieri has nothing to disclose. Conflict of interest: B.T. Thompson reports personal fees from Bayer, Thetis and Novartis, outside the submitted work. Conflict of interest: H. Wrigge reports personal fees for consultancy from Dräger Medical, personal fees for advisory board work from Liberate Medical, grants and personal fees for lectures from InfectoPharm, personal fees for lectures from MSD and GE, outside the submitted work. Conflict of interest: L.J. Brochard reports grants from Medtronic Covidien, grants and non-financial support from Fisher Paykel, non-financial support from Air Liquide, Sentec and Philips, other (patent) from General Electric, outside the submitted work. Conflict of interest: J.G. Laffey reports grants and personal fees from Baxter, grants and non-financial support from Aerogen and Factor Biosciences, outside the submitted work., (Copyright ©ERS 2021.)

Background: Diaphragmatic respiratory effort during mechanical ventilation is an important determinant of patient outcome, but direct measurement of diaphragmatic contractility requires specialized instrumentation and technical expertise. We sought to determine whether routinely collected clinical variables can predict diaphragmatic contractility and stratify the risk of diaphragm atrophy., Methods: We conducted a secondary analysis of a prospective cohort study on diaphragm ultrasound in mechanically ventilated subjects. Clinical variables, such as breathing frequency, ventilator settings, and blood gases, were recorded longitudinally. Machine learning techniques were used to identify variables predicting diaphragm contractility and stratifying the risk of diaphragm atrophy (> 10% decrease in thickness from baseline). Performance of the variables was evaluated in mixed-effects logistic regression and random-effects tree models using the area under the receiver operating characteristic curve., Results: Measurements were available for 761 study days in 191 subjects, of whom 73 (38%) developed diaphragm atrophy. No routinely collected clinical variable, alone or in combination, could accurately predict either diaphragm contractility or the development of diaphragm atrophy (model area under the receiver operating characteristic curve 0.63-0.75). The risk of diaphragm atrophy was not significantly different according to the presence or absence of patient-triggered breaths (38.3% vs 38.6%; odds ratio 1.01, 95% CI 0.05-2.03). Diaphragm thickening fraction < 15% during either of the first 2 d of the study was associated with a higher risk of atrophy (44.6% vs 26.1%; odds ratio 2.28, 95% CI 1.05-4.95)., Conclusions: Diaphragmatic contractility and the risk of diaphragm atrophy could not be reliably determined from routinely collected clinical variables and ventilator settings. A single measurement of diaphragm thickening fraction measured within 48 h of initiating mechanical ventilation can be used to stratify the risk of diaphragm atrophy during mechanical ventilation., (Copyright © 2021 by Daedalus Enterprises.)

Background: Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice., Methods: Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ 2 ) test (p < 0·05 was considered as unstable)., Results: Agreement was achieved for 27 (73%) management strategies which were then used to develop expert clinical practice statements. Experts agreed that COVID-19-related acute respiratory distress syndrome (ARDS) is clinically similar to other forms of ARDS. The Delphi process yielded strong suggestions for use of systemic corticosteroids for critical COVID-19; awake self-proning to improve oxygenation and high flow nasal oxygen to potentially reduce tracheal intubation; non-invasive ventilation for patients with mixed hypoxemic-hypercapnic respiratory failure; tracheal intubation for poor mentation, hemodynamic instability or severe hypoxemia; closed suction systems; lung protective ventilation; prone ventilation (for 16-24 h per day) to improve oxygenation; neuromuscular blocking agents for patient-ventilator dyssynchrony; avoiding delay in extubation for the risk of reintubation; and similar timing of tracheostomy as in non-COVID-19 patients. There was no agreement on positive end expiratory pressure titration or the choice of personal protective equipment., Conclusion: Using a Delphi method, an agreement among experts was reached for 27 statements from which 20 expert clinical practice statements were derived on the respiratory management of C-ARF, addressing important decisions for patient management in areas where evidence is either absent or limited., Trial Registration: The study was registered with Clinical trials.gov Identifier: NCT04534569.

Background: During the COVID-19 pandemic, a need for innovative, inexpensive, and simple ventilator devices for mass use has emerged. The Oxylator (CPR Medical Devices, Markham, Ontario, Canada) is an FDA-approved, fist-size, portable ventilation device developed for out-of-hospital emergency ventilation. It has not been tested in conditions of severe lung injury or with added PEEP. We aimed to assess the performance and reliability of the device in simulated and experimental conditions of severe lung injury, and to derive monitoring methods to allow the delivery of safe, individualized ventilation during situations of surge., Methods: We bench-tested the functioning of the device with an added PEEP valve extensively, mimicking adult patients with various respiratory mechanics during controlled ventilation, spontaneous breathing, and prolonged unstable conditions where mechanics or breathing effort was changed at every breath. The device was further tested on a porcine model (4 animals) after inducing lung injury, and these results were compared with conventional ventilation modes., Results: The device was stable and predictable, delivering a constant flow (30 L/min) and cycling automatically at the inspiratory pressure set (minimum of 20 cm H 2 O) above auto-PEEP. Changes in respiratory mechanics manifested as changes in respiratory timing, allowing prediction of tidal volumes from breathing frequency. Simulating lung injury resulted in relatively low tidal volumes (330 mL with compliance of 20 mL/cm H 2 O). In the porcine model, arterial oxygenation, CO 2 , and pH were comparable to conventional modes of ventilation., Conclusions: The Oxylator is a simple device that delivered stable ventilation with tidal volumes within a clinically acceptable range in bench and porcine lung models with low compliance. External monitoring of respiratory timing is advisable, allowing tidal volume estimation and recognition of changes in respiratory mechanics. The device can be an efficient, low-cost, and practical rescue solution for providing short-term ventilatory support as a temporary bridge, but it requires a caregiver at the bedside., Competing Interests: This work was supported in part by Toronto COVID-19 Action Fund from the University of Toronto and CIHR (FDN143285 and OV3-170344). The Oxylator devices were provided free of charge by CPR Medical Devices; the company played no role in the design and conduct of the study., (Copyright © 2021 by Daedalus Enterprises.)

Background: Acute increases in muscle sonographic echodensity reflect muscle injury. Diaphragm echodensity has not been measured in mechanically ventilated patients. We undertook to develop a technique to characterize changes in diaphragm echodensity during mechanical ventilation and to assess whether these changes are correlated with prolonged mechanical ventilation., Methods: Diaphragm ultrasound images were prospectively collected in mechanically ventilated patients and in 10 young healthy subjects. Echodensity was quantified based on the right-skewed distribution of grayscale values (50th percentile, ED50; 85 th percentile, ED85). Intra- and inter-analyzer measurement reproducibility was determined. Outcomes recorded included duration of ventilation and ICU complications (including reintubation, tracheostomy, prolonged ventilation, or death)., Results: Echodensity measurements were obtained serially in 34 patients comprising a total of 104 images. Baseline (admission) diaphragm ED85 was increased in mechanically ventilated patients compared to younger healthy subjects (median 56, interquartile range (IQR) 42-84, vs. 39, IQR 36-52, p = 0.04). Patients with an initial increase in median echodensity over time (≥ + 10 in ED50 from baseline) had fewer ventilator-free days to day 60 (n = 13, median 46, IQR 0-52) compared to patients without this increase (n = 21, median 53 days, IQR 49-56, unadjusted p = 0.03). Both decreases and increases in diaphragm thickness during mechanical ventilation were associated with increases in ED50 over time (adjusted p = 0.03, conditional R 2  = 0.80) and the association between increase in ED50 and outcomes persisted after adjusting for changes in diaphragm thickness., Conclusions: Many patients exhibit increased diaphragm echodensity at the outset of mechanical ventilation. Increases in diaphragm echodensity during the early course of mechanical ventilation are associated with prolonged mechanical ventilation. Both decreases and increases in diaphragm thickness during mechanical ventilation are associated with increased echodensity.

Background: Excessive respiratory muscle effort during mechanical ventilation may cause patient self-inflicted lung injury and load-induced diaphragm myotrauma, but there are no non-invasive methods to reliably detect elevated transpulmonary driving pressure and elevated respiratory muscle effort during assisted ventilation. We hypothesized that the swing in airway pressure generated by respiratory muscle effort under assisted ventilation when the airway is briefly occluded (ΔP occ ) could be used as a highly feasible non-invasive technique to screen for these conditions., Methods: Respiratory muscle pressure (P mus ), dynamic transpulmonary driving pressure (ΔP L,dyn , the difference between peak and end-expiratory transpulmonary pressure), and ΔP occ were measured daily in mechanically ventilated patients in two ICUs in Toronto, Canada. A conversion factor to predict ΔP L,dyn and P mus from ΔP occ was derived and validated using cross-validation. External validity was assessed in an independent cohort (Nanjing, China)., Results: Fifty-two daily recordings were collected in 16 patients. In this sample, P mus and ΔP L were frequently excessively high: P mus exceeded 10 cm H 2 O on 84% of study days and ΔP L,dyn exceeded 15 cm H 2 O on 53% of study days. ΔP occ measurements accurately detected P mus > 10 cm H 2 O (AUROC 0.92, 95% CI 0.83-0.97) and ΔP L,dyn  > 15 cm H 2 O (AUROC 0.93, 95% CI 0.86-0.99). In the external validation cohort (n = 12), estimating P mus and ΔP L,dyn from ΔP occ measurements detected excessively high P mus and ΔP L,dyn with similar accuracy (AUROC ≥ 0.94)., Conclusions: Measuring ΔP occ enables accurate non-invasive detection of elevated respiratory muscle pressure and transpulmonary driving pressure. Excessive respiratory effort and transpulmonary driving pressure may be frequent in spontaneously breathing ventilated patients.

Background: Patients with initial mild acute respiratory distress syndrome are often underrecognized and mistakenly considered to have low disease severity and favorable outcomes. They represent a relatively poorly characterized population that was only classified as having acute respiratory distress syndrome in the most recent definition. Our primary objective was to describe the natural course and the factors associated with worsening and mortality in this population., Methods: This study analyzed patients from the international prospective Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) who had initial mild acute respiratory distress syndrome in the first day of inclusion. This study defined three groups based on the evolution of severity in the first week: "worsening" if moderate or severe acute respiratory distress syndrome criteria were met, "persisting" if mild acute respiratory distress syndrome criteria were the most severe category, and "improving" if patients did not fulfill acute respiratory distress syndrome criteria any more from day 2., Results: Among 580 patients with initial mild acute respiratory distress syndrome, 18% (103 of 580) continuously improved, 36% (210 of 580) had persisting mild acute respiratory distress syndrome, and 46% (267 of 580) worsened in the first week after acute respiratory distress syndrome onset. Global in-hospital mortality was 30% (172 of 576; specifically 10% [10 of 101], 30% [63 of 210], and 37% [99 of 265] for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively), and the median (interquartile range) duration of mechanical ventilation was 7 (4, 14) days (specifically 3 [2, 5], 7 [4, 14], and 11 [6, 18] days for patients with improving, persisting, and worsening acute respiratory distress syndrome, respectively). Admissions for trauma or pneumonia, higher nonpulmonary sequential organ failure assessment score, lower partial pressure of alveolar oxygen/fraction of inspired oxygen, and higher peak inspiratory pressure were independently associated with worsening., Conclusions: Most patients with initial mild acute respiratory distress syndrome continue to fulfill acute respiratory distress syndrome criteria in the first week, and nearly half worsen in severity. Their mortality is high, particularly in patients with worsening acute respiratory distress syndrome, emphasizing the need for close attention to this patient population.

Rationale: Diaphragm dysfunction worsens outcomes in mechanically ventilated patients, but the clinical impact of potentially preventable changes in diaphragm structure and function caused by mechanical ventilation is unknown., Objectives: To determine whether diaphragm atrophy developing during mechanical ventilation leads to prolonged ventilation., Methods: Diaphragm thickness was measured daily by ultrasound in adults requiring invasive mechanical ventilation; inspiratory effort was assessed by thickening fraction. The primary outcome was time to liberation from ventilation. Secondary outcomes included complications (reintubation, tracheostomy, prolonged ventilation, or death). Associations were adjusted for age, severity of illness, sepsis, sedation, neuromuscular blockade, and comorbidity., Measurements and Main Results: Of 211 patients enrolled, 191 had two or more diaphragm thickness measurements. Thickness decreased more than 10% in 78 patients (41%) by median Day 4 (interquartile range, 3-5). Development of decreased thickness was associated with a lower daily probability of liberation from ventilation (adjusted hazard ratio, 0.69; 95% confidence interval [CI], 0.54-0.87; per 10% decrease), prolonged ICU admission (adjusted duration ratio, 1.71; 95% CI, 1.29-2.27), and a higher risk of complications (adjusted odds ratio, 3.00; 95% CI, 1.34-6.72). Development of increased thickness (n = 47; 24%) also predicted prolonged ventilation (adjusted duration ratio, 1.38; 95% CI, 1.00-1.90). Decreasing thickness was related to abnormally low inspiratory effort; increasing thickness was related to excessive effort. Patients with thickening fraction between 15% and 30% (similar to breathing at rest) during the first 3 days had the shortest duration of ventilation., Conclusions: Diaphragm atrophy developing during mechanical ventilation strongly impacts clinical outcomes. Targeting an inspiratory effort level similar to that of healthy subjects at rest might accelerate liberation from ventilation.

Acute respiratory distress syndrome is a multifactorial lung injury that continues to be associated with high levels of morbidity and mortality. Mechanical ventilation, although lifesaving, is associated with new iatrogenic injury. Current best practice involves the use of small Vt, low plateau and driving pressures, and high levels of positive end-expiratory pressure. Collectively, these interventions are termed "lung-protective ventilation." Recent investigations suggest that individualized measurements of pulmonary mechanical variables rather than population-based ventilation prescriptions may be used to set the ventilator with the potential to improve outcomes beyond those achieved with standard lung protective ventilation. This review outlines the measurement and application of clinically applicable pulmonary mechanical concepts, such as plateau pressures, driving pressure, transpulmonary pressures, stress index, and measurement of strain. In addition, the concept of the "baby lung" and the utility of dynamic in addition to static measures of pulmonary mechanical variables are discussed.

Mechanical ventilation is the most used short-term life support technique worldwide and is applied daily for a diverse spectrum of indications, from scheduled surgical procedures to acute organ failure. This state-of-the-art review provides an update on the basic physiology of respiratory mechanics, the working principles, and the main ventilatory settings, as well as the potential complications of mechanical ventilation. Specific ventilatory approaches in particular situations such as acute respiratory distress syndrome and chronic obstructive pulmonary disease are detailed along with protective ventilation in patients with normal lungs. We also highlight recent data on patient-ventilator dyssynchrony, humidified high-flow oxygen through nasal cannula, extracorporeal life support, and the weaning phase. Finally, we discuss the future of mechanical ventilation, addressing avenues for improvement., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Excessively deep sedation is prevalent in mechanically ventilated patients and often considered suboptimal. We hypothesized that the bispectral index (BIS), a quantified electroencephalogram instrument, would accurately detect deep levels of sedation., Methods: We prospectively enrolled 90 critically ill mechanically ventilated patients who were receiving sedation. The BIS was monitored for 24 hours and compared with the Richmond Agitation Sedation Scale (RASS) evaluated every 4 hours. Deep sedation was defined as a RASS of -3 to -5. Threshold values of baseline BIS (the lowest value before RASS assessment) and stimulated BIS (the highest value after standardized assessment) for detecting deep sedation were determined in a training set (45 patients, 262 RASS assessments). Diagnostic accuracy was then analyzed in a validation set (45 patients, 264 RASS assessments)., Results: Deep sedation was only prescribed in 6 (6.7%) patients, but 76 patients (84.4%) had at least 1 episode of deep sedation. Thresholds for detecting deep sedation of 50 for baseline and 80 for stimulated BIS were identified, with respective areas under the receiver-operating characteristic curve of 0.771 (95% confidence interval, 0.714-0.828) and 0.805 (0.752-0.857). The sensitivity and specificity of baseline BIS were 94.0% and 66.5% and of stimulated BIS were 91.0% and 66.5%. When baseline and stimulated BIS were combined, the sensitivity, specificity, and clinical utility index were 85.0% (76.1%-91.1%), 85.9% (79.5%-90.7%), and 66.9% (57.8%-76.0%), respectively., Conclusions: Combining baseline and stimulated BIS may help detect deep sedation in mechanically ventilated patients.

Background: The effect of alternative spontaneous breathing trial (SBT) techniques on extubation success and other clinically important outcomes is uncertain., Methods: We searched MEDLINE, EMBASE, CENTRAL, CINAHL, Evidence-Based Medicine Reviews, Ovid Health Star, proceedings of five conferences (1990-2016), and reference lists for randomized trials comparing SBT techniques in intubated adults or children. Primary outcomes were initial SBT success, extubation success, or reintubation. Two reviewers independently screened citations, assessed trial quality, and abstracted data., Results: We identified 31 trials (n = 3541 patients). Moderate-quality evidence showed that patients undergoing pressure support (PS) compared with T-piece SBTs (nine trials, n = 1901) were as likely to pass an initial SBT (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.89-1.11; I 2  = 77%) but more likely to be ultimately extubated successfully (RR 1.06, 95% CI 1.02-1.10; 11 trials, n = 1904; I 2  = 0%). Exclusion of one trial with inconsistent results for SBT and extubation outcomes suggested that PS (vs T-piece) SBTs also improved initial SBT success (RR 1.06, 95% CI 1.01-1.12; I 2  = 0%). Limited data suggest that automatic tube compensation plus continuous positive airway pressure (CPAP) vs CPAP alone or PS increase SBT but not extubation success., Conclusions: Patients undergoing PS (vs T-piece) SBTs appear to be 6% (95% CI 2-10%) more likely to be extubated successfully and, if the results of an outlier trial are excluded, 6% (95% CI 1-12%) more likely to pass an SBT. Future trials should investigate patients for whom SBT and extubation outcomes are uncertain and compare techniques that maximize differences in support.

Background: This document provides evidence-based clinical practice guidelines on the use of mechanical ventilation in adult patients with acute respiratory distress syndrome (ARDS)., Methods: A multidisciplinary panel conducted systematic reviews and metaanalyses of the relevant research and applied Grading of Recommendations, Assessment, Development, and Evaluation methodology for clinical recommendations., Results: For all patients with ARDS, the recommendation is strong for mechanical ventilation using lower tidal volumes (4-8 ml/kg predicted body weight) and lower inspiratory pressures (plateau pressure < 30 cm H 2 O) (moderate confidence in effect estimates). For patients with severe ARDS, the recommendation is strong for prone positioning for more than 12 h/d (moderate confidence in effect estimates). For patients with moderate or severe ARDS, the recommendation is strong against routine use of high-frequency oscillatory ventilation (high confidence in effect estimates) and conditional for higher positive end-expiratory pressure (moderate confidence in effect estimates) and recruitment maneuvers (low confidence in effect estimates). Additional evidence is necessary to make a definitive recommendation for or against the use of extracorporeal membrane oxygenation in patients with severe ARDS., Conclusions: The panel formulated and provided the rationale for recommendations on selected ventilatory interventions for adult patients with ARDS. Clinicians managing patients with ARDS should personalize decisions for their patients, particularly regarding the conditional recommendations in this guideline.

Rationale: Controlled mechanical ventilation is used to deliver lung-protective ventilation in patients with acute respiratory distress syndrome. Despite recognized benefits, such as preserved diaphragm activity, partial support ventilation modes may be incompatible with lung-protective ventilation due to high Vt and high transpulmonary pressure. As an alternative to high-dose sedatives and controlled mechanical ventilation, pharmacologically induced neuromechanical uncoupling of the diaphragm should facilitate lung-protective ventilation under partial support modes., Objectives: To investigate whether partial neuromuscular blockade can facilitate lung-protective ventilation while maintaining diaphragm activity under partial ventilatory support., Methods: In a proof-of-concept study, we enrolled 10 patients with lung injury and a Vt greater than 8 ml/kg under pressure support ventilation (PSV) and under sedation. After baseline measurements, rocuronium administration was titrated to a target Vt of 6 ml/kg during neurally adjusted ventilatory assist (NAVA). Thereafter, patients were ventilated in PSV and NAVA under continuous rocuronium infusion for 2 hours. Respiratory parameters, hemodynamic parameters, and blood gas values were measured., Measurements and Main Results: Rocuronium titration resulted in significant declines of Vt (mean ± SEM, 9.3 ± 0.6 to 5.6 ± 0.2 ml/kg; P < 0.0001), transpulmonary pressure (26.7 ± 2.5 to 10.7 ± 1.2 cm H 2 O; P < 0.0001), and diaphragm electrical activity (17.4 ± 2.3 to 4.5 ± 0.7 μV; P < 0.0001), and could be maintained under continuous rocuronium infusion. During titration, pH decreased (7.42 ± 0.02 to 7.35 ± 0.02; P < 0.0001), and mean arterial blood pressure increased (84 ± 6 to 99 ± 6 mm Hg; P = 0.0004), as did heart rate (83 ± 7 to 93 ± 8 beats/min; P = 0.0004)., Conclusions: Partial neuromuscular blockade facilitates lung-protective ventilation during partial ventilatory support, while maintaining diaphragm activity, in sedated patients with lung injury.

Rationale: Diaphragm atrophy and dysfunction have been reported in humans during mechanical ventilation, but the prevalence, causes, and functional impact of changes in diaphragm thickness during routine mechanical ventilation for critically ill patients are unknown., Objectives: To describe the evolution of diaphragm thickness over time during mechanical ventilation, its impact on diaphragm function, and the influence of inspiratory effort on this phenomenon., Methods: In three academic intensive care units, 107 patients were enrolled shortly after initiating ventilation along with 10 nonventilated intensive care unit patients (control subjects). Diaphragm thickness and contractile activity (quantified by the inspiratory thickening fraction) were measured daily by ultrasound., Measurements and Main Results: Over the first week of ventilation, diaphragm thickness decreased by more than 10% in 47 (44%), was unchanged in 47 (44%), and increased by more than 10% in 13 (12%). Thickness did not vary over time following extubation or in nonventilated patients. Low diaphragm contractile activity was associated with rapid decreases in diaphragm thickness, whereas high contractile activity was associated with increases in diaphragm thickness (P = 0.002). Contractile activity decreased with increasing ventilator driving pressure (P = 0.01) and controlled ventilator modes (P = 0.02). Maximal thickening fraction (a measure of diaphragm function) was lower in patients with decreased or increased diaphragm thickness (n = 10) compared with patients with unchanged thickness (n = 10; P = 0.05 for comparison)., Conclusions: Changes in diaphragm thickness are common during mechanical ventilation and may be associated with diaphragmatic weakness. Titrating ventilatory support to maintain normal levels of inspiratory effort may prevent changes in diaphragm configuration associated with mechanical ventilation.

Rationale: Previous trials of higher positive end-expiratory pressure (PEEP) for acute respiratory distress syndrome (ARDS) failed to demonstrate mortality benefit, possibly because of differences in lung recruitability among patients with ARDS., Objectives: To determine whether the physiological response to increased PEEP is associated with mortality., Methods: In a secondary analysis of the Lung Open Ventilation Study (LOVS, n = 983), we examined the relationship between the initial response to changes in PEEP after randomization and mortality. We sought to corroborate our findings using data from a different trial of higher PEEP (ExPress, n = 749)., Measurements and Main Results: The oxygenation response (change in ratio of arterial partial pressure of oxygen to fraction of inspired oxygen: P/F) after the initial change in PEEP after randomization varied widely (median, 9.5 mm Hg; interquartile range, -16 to 47) and was only weakly related to baseline P/F or the magnitude of PEEP change. Among patients in whom PEEP was increased after randomization, an increase in P/F was associated with reduced mortality (multivariable logistic regression; adjusted odds ratio, 0.80 [95% confidence interval, 0.72-0.89] per 25-mm Hg increase in P/F), particularly in patients with severe disease (baseline P/F [less-than-or-equal-to] 150 mm Hg). Changes in compliance and dead space were not associated with mortality. These findings were confirmed by a similar analysis of data from the ExPress trial., Conclusions: Patients with ARDS who respond to increased PEEP by improved oxygenation have a lower risk of death. The oxygenation response to PEEP might be used to predict whether patients will benefit from higher versus lower PEEP.

Background: The arterial partial pressure of CO(2) (P(aCO(2))) can be grossly estimated by the end-tidal partial pressure of CO(2) (P(ETCO(2))). This principle is used in SmartCare (Dräger, Lübeck, Germany), which is an automated closed-loop system that uses P(ETCO(2)) to estimate alveolar ventilation during mechanical ventilation., Objective: To assess whether the maximum P(ETCO(2)) value (instead of the averaged P(ETCO(2)) value) over 2-min or 5-min periods improves P(aCO(2)) estimation, and determine the consequences for the SmartCare system., Methods: We continuously monitored breath-by-breath P(ETCO(2)) during ventilation with SmartCare in 36 patients mechanically ventilated for various disorders, including 14 patients with COPD. Data were collected simultaneously from SmartCare recordings, every 2 min or 5 min, and through a dedicated software that recorded ventilation data every 10 s. We compared the maximum and averaged P(ETCO(2)) values over 2-min and 5-min periods to the P(aCO(2)) measured from 80 arterial blood samples clinically indicated in 26 patients. We also compared SmartCare's classifications of patient ventilatory status based on averaged P(ETCO(2)) values to what the classifications would have been with the maximum P(ETCO(2)) values., Results: Mean P(aCO(2)) was 44 ± 11 mm Hg. P(aCO(2)) was higher than averaged P(ETCO(2)) by 10 ± 6 mm Hg, and this difference was reduced to 6 ± 6 mm Hg with maximum P(ETCO(2)). The results were similar whether patients had COPD or not. Very few aberrant values (< 0.01%) needed to be discarded. Among the 3,137 classifications made by the SmartCare system, 1.6% were changed by using the maximum P(ETCO(2)) value instead of the averaged P(ETCO(2)) value., Conclusions: Use of maximum P(ETCO(2)) reduces the difference between P(aCO(2)) and P(ETCO(2)) and improves SmartCare's classification of patient ventilatory status.