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Rationale: Early mobilization of ECMO-supported patients is increasingly common, but it remains unknown whether there are factors predictive of achieving higher intensity mobilization among those a...

Rationale: Respiratory muscle weakness is common in critically ill patients; the role of targeted inspiratory muscle training (IMT) in intensive care unit rehabilitation strategies remains poorly defined. Objectives: The primary objective of the present study was to describe the range and tolerability of published methods for IMT. The secondary objectives were to determine whether IMT improves respiratory muscle strength and clinical outcomes in critically ill patients. Methods: We conducted a systematic review to identify randomized and nonrandomized studies of physical rehabilitation interventions intended to strengthen the respiratory muscles in critically ill adults. We searched the MEDLINE, Embase, HealthSTAR, CINAHL, and CENTRAL databases (inception to September Week 3, 2017) and conference proceedings (2012 to 2017). Data were independently extracted by two authors and collected on a standardized report form. Results: A total of 28 studies (N = 1,185 patients) were included. IMT was initiated during early mechanical ventilation (8 studies), after patients proved difficult to wean (14 studies), or after extubation (3 studies), and 3 other studies did not report exact timing. Threshold loading was the most common technique; 13 studies employed strength training regimens, 11 studies employed endurance training regimens, and 4 could not be classified. IMT was feasible, and there were few adverse events during IMT sessions (nine studies; median, 0%; interquartile range, 0–0%). In randomized trials (n = 20), IMT improved maximal inspiratory pressure compared with control (15 trials; mean increase, 6 cm H(2)O; 95% confidence interval [CI], 5–8 cm H(2)O; pooled relative ratio of means, 1.19; 95% CI, 1.14–1.25) and maximal expiratory pressure (4 trials; mean increase, 9 cm H(2)O; 95% CI, 5–14 cm H(2)O). IMT was associated with a shorter duration of ventilation (nine trials; mean difference, 4.1 d; 95% CI, 0.8–7.4 d) and a shorter duration of weaning (eight trials; mean difference, 2.3 d; 95% CI, 0.7–4.0 d), but confidence in these pooled estimates was low owing to methodological limitations, including substantial statistical and methodological heterogeneity. Conclusions: Most studies of IMT in critically ill patients have employed inspiratory threshold loading. IMT is feasible and well tolerated in critically ill patients and improves both inspiratory and expiratory muscle strength. The impact of IMT on clinical outcomes requires future confirmation.

Rationale: Several studies have explored the experiences of ventilator-assisted individuals living at home with family caregivers. However, few explore the experiences of these individuals as they ...

By minimizing tidal lung strain and maintaining alveolar recruitment, high-frequency oscillatory ventilation (HFOV) may protect against ventilator-induced lung injury.To summarize the current evidence in support of the use of HFOV in adult patients with acute respiratory distress syndrome.We conducted a systematic review and meta-analysis of randomized trials comparing mortality rates with the use of HFOV versus conventional mechanical ventilation for adult patients with acute respiratory distress syndrome. Eligible trials were identified from previously published systematic reviews and an updated literature search. Data on 28-day mortality, oxygenation, adverse events, and use of rescue therapies were collected; effects were pooled using random effects models weighted by inverse variance. Strength of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation methodology.Six trials were eligible for inclusion (total n = 1,715 patients). Four trials mandated lung-protective ventilation in the control group and one trial applied a higher positive end-expiratory pressure (PEEP) ventilation strategy in the control group. None of the trials were judged to be at high risk of bias, though all were unblinded. In trials that did not systematically employ any cointerventions with HFOV and that targeted low tidal volumes in the patients randomized to conventional ventilation (primary analysis), HFOV had no significant effect on mortality (three trials; risk ratio [RR], 1.14; 95% confidence interval [CI], 0.88 to 1.48; evidence grade = high). Pooled analysis of all six trials also did not suggest a significant mortality reduction (RR, 0.94; 95% CI, 0.71 to 1.24; evidence grade = low). The single trial that employed a conventional ventilation strategy with both lower tidal volumes and higher PEEP as control reported higher mortality in patients receiving HFOV (RR, 1.41; 95% CI, 1.12 to 1.79). HFOV was not associated with improved oxygenation after 24 hours (five trials; mean increase of 10 mm Hg; 95% CI, -16 to 37 mm Hg). Rates of barotrauma were not different between HFOV and conventional ventilation, although significant benefit or harm could not be excluded (RR, 1.15; 95% CI, 0.61 to 2.17).Published randomized trials suggest that HFOV is not associated with a mortality benefit, and may even be harmful in comparison to ventilation with low tidal volumes and higher levels of PEEP.

Higher positive end-expiratory pressure (PEEP) levels may reduce atelectrauma, but increase over-distention lung injury. Whether higher PEEP improves clinical outcomes among patients with acute respiratory distress syndrome (ARDS) is unclear.To compare clinical outcomes of mechanical ventilation strategies using higher PEEP levels versus lower PEEP strategies in patients with ARDS.We performed a systematic review and meta-analysis of clinical trials investigating mechanical ventilation strategies using higher versus lower PEEP levels. We used random effects models to evaluate the effect of higher PEEP on 28-day mortality, organ failure, ventilator-free days, barotrauma, oxygenation, and ventilation.We identified eight randomized trials comparing higher versus lower PEEP strategies, enrolling 2,728 patients with ARDS. Patients were 55 (±16) (mean ± SD) years old and 61% were men. Mean PEEP in the higher PEEP groups was 15.1 (±3.6) cm HUse of higher PEEP is unlikely to improve clinical outcomes among unselected patients with ARDS.

In patients with acute respiratory distress syndrome (ARDS), lung recruitment maneuvers (LRMs) may prevent ventilator-induced lung injury and improve survival.To summarize the current evidence in support of the use of LRMs in adult patients with ARDS and to inform the recently published American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine clinical practice guideline on mechanical ventilation in ARDS.We conducted a systematic review and meta-analysis of randomized trials comparing mechanical ventilation strategies with and without LRMs. Eligible trials were identified from among previously published systematic reviews and an updated literature search. Data on 28-day mortality, oxygenation, adverse events, and use of rescue therapy were collected, and results were pooled using random effects models weighted by inverse variance. Strength of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology.We screened 430 citations and previous systematic reviews and found six trials eligible for inclusion (n = 1,423 patients in total). The type of LRM varied widely between trials, and five of the trials involved a cointervention with a higher positive end-expiratory pressure (PEEP) ventilation strategy. Risk of bias was deemed high in one trial. In the primary analysis, the only trial without a cointervention showed that LRMs were associated with reduced mortality (one trial; risk ratio [RR], 0.62; 95% confidence interval [CI], 0.39-0.98; evidence grade = low). Meta-analysis of all six trials also suggested a significant mortality reduction (six trials; RR, 0.81; 95% CI, 0.69-0.95; evidence grade = moderate), and the use of a higher PEEP cointervention did not significantly modify the mortality effect (P = 0.27 for heterogeneity). LRMs were also associated with improved oxygenation after 24 hours (six trials; mean increase, 52 mm Hg; 95% CI, 23-81 mm Hg) and less frequent requirement for rescue therapy (three trials; RR, 0.65; 95% CI, 0.45-0.94). LRMs were not associated with an increased rate of barotrauma (four trials; RR, 0.84; 95% CI, 0.46-1.55). The rate of hemodynamic compromise was not significantly increased with LRMs (three trials; RR, 1.30; 95% CI, 0.92-1.78).Randomized trials suggest that LRMs in combination with a higher PEEP ventilation strategy reduce mortality, but confidence in this finding is limited. Further trials are required to confirm benefit from LRMs in adults with ARDS.

There are limited data on physiotherapy during extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS).We sought to characterize physiotherapy delivered to patients with ARDS supported with ECMO, as well as to evaluate the association of this therapeutic modality with mortality.We conducted a retrospective cohort study of all adult patients with ARDS supported with ECMO at our institution between 2010 and 2015. The highest level of daily activity while on ECMO was coded using the ICU Mobility Scale. Through multivariable logistic regression, we evaluated the association between intensive care unit (ICU) physiotherapy and ICU mortality. In an exploratory univariate analysis, we also evaluated factors associated with a higher intensity of ICU rehabilitation while on ECMO.Of 107 patients who underwent ECMO, 61 (57%) had ARDS requiring venovenous ECMO. The ICU physiotherapy team was consulted for 82% (n = 50) of patients. Thirty-nine percent (n = 18) of these patients achieved an activity level of 2 or higher (active exercises in bed), and 17% (n = 8) achieved an activity level 4 or higher (actively sitting over the side of the bed). In an exploratory analysis, consultation with the ICU physiotherapy team was associated with decreased ICU mortality (odds ratio, 0.19; 95% confidence interval, 0.04-0.98). In univariate analysis, severity-of-illness factors differentiated higher-intensity and lower-intensity physiotherapy.Physiotherapy during ECMO is feasible and safe when performed by an experienced team and executed in stages. Although our study suggests an association with improved ICU mortality, future research is needed to identify potential barriers, optimal timing, dosage, and safety profile.

Rationale: Adoption and de-adoption of adjuvant strategies to mechanical ventilation for acute respiratory failure (ARF), and factors associated with their selection, have not been extensively evaluated.Objectives: To evaluate change in use of adjuvants to mechanical ventilation for ARF (2008–2013), the impact of landmark publications on adoption and de-adoption, and factors associated with use.Methods: Changes in use of four adjuvants for ARF from 2008 to 2013, the impact of landmark publications on use, and factors associated with use were evaluated with the Premier Database. Extracorporeal membrane oxygenation (ECMO), inhaled nitric oxide, inhaled epoprostenol, and continuous neuromuscular blockading agents (cNMBAs) in adult mechanically ventilated patients were identified on the basis of International Classification of Diseases, Ninth Revision, Clinical Modification codes and billing data.Measurements and Main Results: Among 514,913 patients with ARF, 11,567 (2.3%) were treated with at least one adjuv...

The optimal anticoagulation strategy for venovenous extracorporeal membrane oxygenation (VV-ECMO) is not known.To evaluate the safety of anticoagulation strategies and monitoring during VV-ECMO for respiratory failure.We conducted a systematic review to evaluate the association between anticoagulation strategies during VV-ECMO and prespecified outcomes, including major bleeding episodes, thrombotic events, and in-hospital mortality. We included articles published between 1977 and January 30, 2015. Study quality was assessed using the Newcastle-Ottawa scoring system. A separate meta-analysis was not planned.Data were independently extracted by two authors and collected on a standardized report form.A total of 18 studies (n = 646) were included; 17 studies enrolled patients with acute respiratory distress syndrome. Across all studies, the duration of VV-ECMO support ranged from 4 to 20 days. Patients received an average of 2.3 (±3.9) units of transfused red blood cells per day. The bleeding rate across all studies was 16%, and the rate of thrombosis was 53%. Among seven studies (199 patients) targeting a specified activated partial thromboplastin time (aPTT), there were 37 (19%) major bleeding episodes and 53 (27%) major thromboses. Among five studies (43 patients) with aPTT targets of 60 seconds or greater, there were 24 (56%) bleeding episodes and 3 (7%) clotting events. Three studies (156 patients) with an aPTT target under 60 seconds reported 13 (8%) and 50 (32%) significant bleeding and thrombotic events, respectively. The most commonly reported thrombotic events were circuit-related clotting and deep-vein thrombosis. Mortality during VV-ECMO varied across the studies, ranging from 0 to at least 50% at heterogeneous time points. The total number of deaths for all studies combined was 186 (29%).The role and optimal therapeutic targets for anticoagulation during VV-ECMO are unclear. Previously published studies are limited by retrospective, observational design, small cohorts, and patient heterogeneity. The clinical significance of reported thrombotic complications is largely unknown. This systematic review underscores the need for randomized controlled trials of anticoagulation strategies for patients undergoing VV-ECMO for respiratory failure.

Rationale: Low–tidal volume ventilation (LTVV; 6 ml/kg) benefits patients with acute respiratory distress syndrome and may aid those with other causes of respiratory failure. Current early ventilation practices are poorly defined. Objectives: We observed patients with acute respiratory failure to assess the feasibility of a pragmatic trial of LTVV and to guide experimental design. Methods: We prospectively enrolled consecutive patients with acute respiratory failure admitted to intensive care units expected to participate in the proposed trial. We collected clinical data as well as information on initial and daily ventilator settings and inpatient mortality. We estimated the benefit of LTVV using predictive linear and nonlinear models. We simulated models to estimate power and feasibility of a cluster-randomized trial of LTVV versus usual care in acute respiratory failure. Results: We included 2,484 newly mechanically ventilated patients (31% with acute respiratory distress syndrome) from 49 hospitals. Hospital mortality was 28%. Mean initial tidal volume was 7.1 ml/kg predicted body weight (95% confidence interval, 7.1–7.2), with 78% of patients receiving tidal volumes less than or equal to 8 ml/kg. Our models estimated a mortality benefit of 0–2% from LTVV compared with usual care. Simulation of a stepped-wedged cluster-randomized trial suggested that enrollment of 106,361 patients would be necessary to achieve greater than 90% power. Conclusions: Use of initial tidal volumes less than 8 ml/kg predicted body weight was common at hospitals participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. After considering the size and budgetary requirement for a cluster-randomized trial of LTVV versus usual care in acute respiratory failure, the PETAL Network deemed the proposed trial infeasible. A rapid observational study and simulations to model anticipated power may help better design trials.

Rationale: The application of prone positioning for acute respiratory distress syndrome (ARDS) has evolved, with recent trials focusing on patients with more severe ARDS, and applying prone ventilation for more prolonged periods. Objectives: This review evaluates the effect of prone positioning on 28-day mortality (primary outcome) compared with conventional mechanical ventilation in the supine position for adults with ARDS. Methods: We updated the literature search from a systematic review published in 2010, searching MEDLINE, EMBASE, and CENTRAL (through to August 2016). We included randomized, controlled trials (RCTs) comparing prone to supine positioning in mechanically ventilated adults with ARDS, and conducted sensitivity analyses to explore the effects of duration of prone ventilation, concurrent lung-protective ventilation and ARDS severity. Secondary outcomes included PaO2/FIO2 ratio on Day 4 and an evaluation of adverse events. Meta-analyses used random effects models. Methodologic quality of the RCTs was evaluated using the Cochrane risk of bias instrument, and methodologic quality of the overall body of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) guidelines. Results: Eight RCTs fulfilled entry criteria, and included 2,129 patients (1,093 [51%] proned). Meta-analysis revealed no difference in mortality (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.68–1.04), but subgroup analyses found lower mortality with 12 hours or greater duration prone (five trials; RR, 0.74; 95% CI, 0.56–0.99) and for patients with moderate to severe ARDS (five trials; RR, 0.74; 95% CI, 0.56–0.99). PaO2/FIO2 ratio on Day 4 for all patients was significantly higher in the prone positioning group (mean difference, 23.5; 95% CI, 12.4–34.5). Prone positioning was associated with higher rates of endotracheal tube obstruction and pressure sores. Risk of bias was low across the trials. Conclusions: Prone positioning is likely to reduce mortality among patients with severe ARDS when applied for at least 12 hours daily. Copyright © 2017 by the American Thoracic Society.

The American Thoracic Society/European Society for Intensive Care Medicine/Society of Critical Care Medicine guidelines on mechanical ventilation in adult patients with acute respiratory distress syndrome (ARDS) provide treatment recommendations derived from a thorough analysis of the clinical evidence on six clinical interventions. However, each of the recommendations contains areas of uncertainty and controversy, which may affect their appropriate clinical application.To provide a critical review of the experimental evidence surrounding the pathophysiology of ventilator-induced lung injury and to help clinicians apply the clinical recommendations to individual patients.We conducted a literature search and narrative review.A large number of experimental studies have been performed with the aim of improving understanding of the pathophysiological effects of mechanical ventilation. These studies have formed the basis for the design of many clinical trials. Translational research has fundamentally advanced understanding of the mechanisms of ventilator-induced lung injury, thus informing the design of interventions that improve survival in patients with ARDS.Because daily management of patients with ARDS presents the challenge of competing considerations, clinicians should consider the mechanism of ventilator-induced lung injury, as well as the rationale for interventions designed to mitigate it, when applying evidence-based recommendations at the bedside.

Trials investigating use of lower tidal volumes and inspiratory pressures for patients with acute respiratory distress syndrome (ARDS) have shown mixed results.To compare clinical outcomes of mechanical ventilation strategies that limit tidal volumes and inspiratory pressures (LTV) to strategies with tidal volumes of 10 to 15 ml/kg among patients with ARDS.This is a systematic review and meta-analysis of clinical trials investigating LTV mechanical ventilation strategies. We used random effects models to evaluate the effect of LTV on 28-day mortality, organ failure, ventilator-free days, barotrauma, oxygenation, and ventilation. Our primary analysis excluded trials for which the LTV strategy was combined with the additional strategy of higher positive end-expiratory pressure (PEEP), but these trials were included in a stratified sensitivity analysis. We performed metaregression of tidal volume gradient achieved between intervention and control groups on mortality effect estimates. We used Grading of Recommendations Assessment, Development, and Evaluation methodology to determine the quality of evidence.Seven randomized trials involving 1,481 patients met eligibility criteria for this review. Mortality was not significantly lower for patients receiving an LTV strategy (33.6%) as compared with control strategies (40.4%) (relative risk [RR], 0.87; 95% confidence interval [CI], 0.70-1.08; heterogeneity statistic IThe trend toward lower mortality with LTV ventilation in the primary analysis and the significant relationship between the degree of tidal volume reduction and the mortality effect together suggest, but do not prove, that LTV ventilation improves mortality among critically ill adults with ARDS.

Rationale: Extracorporeal life support (ECLS) for acute respiratory failure has increased as a result of technological advancements and promising results from recent studies as compared with historical trials.Objectives: Systematically review the effect of ECLS compared with mechanical ventilation on mortality, length of stay, and adverse events in respiratory failure.Methods: Data sources included were MEDLINE, EMBASE, and CENTRAL (through to October 2013). Any randomized controlled trial (RCT) or observational study comparing ECLS to mechanical ventilation in adults was used. Two authors independently abstracted the data. Our primary outcome was mortality. Secondary outcomes included intensive care unit length of stay, hospital length of stay, and adverse events. A sensitivity analysis was performed restricted to RCTs and quasi-RCTs, and a number of predefined subgroups were identified to explore heterogeneity.Measurements and Main Results: Ten studies (four RCTs, six observational studies, 1,248 patien...

Extracorporeal life support (ECLS) for acute respiratory failure has increased as a result of technological advancements and promising results from recent studies as compared with historical trials.Systematically review the effect of ECLS compared with mechanical ventilation on mortality, length of stay, and adverse events in respiratory failure.Data sources included were MEDLINE, EMBASE, and CENTRAL (through to October 2013). Any randomized controlled trial (RCT) or observational study comparing ECLS to mechanical ventilation in adults was used. Two authors independently abstracted the data. Our primary outcome was mortality. Secondary outcomes included intensive care unit length of stay, hospital length of stay, and adverse events. A sensitivity analysis was performed restricted to RCTs and quasi-RCTs, and a number of predefined subgroups were identified to explore heterogeneity.Ten studies (four RCTs, six observational studies, 1,248 patients) were included. There was no significant difference in hospital mortality with ECLS as compared with mechanical ventilation (risk ratio [RR], 1.02; 95% confidence interval [CI], 0.79-1.33; I(2) = 77%). When restricted to venovenous ECLS studies of randomized trials and quasi-randomized trials (three studies; 504 patients), there was a decrease in mortality with ECLS compared with mechanical ventilation (RR, 0.64; 95% CI, 0.51-0.79; I(2) = 15%). There were insufficient study-level data to evaluate most secondary outcomes. Bleeding was significantly greater in the ECLS group (RR, 11.44; 95% CI, 3.11-42.06; I(2) = 0%). In the H1N1 subgroup (three studies; 364 patients), ECLS was associated with significantly lower hospital mortality (RR, 0.62; 95% CI, 0.45-0.8; I(2) = 25%).ECLS was not associated with a mortality benefit in patients with acute respiratory failure. However, a significant mortality benefit was seen when restricted to higher-quality studies of venovenous ECLS. Patients with H1N1-acute respiratory distress syndrome represent a subgroup that may benefit from ECLS. Future studies are needed to confirm the efficacy of ECLS as well as the optimal configuration, indications, and timing for adult patients with respiratory failure.

In patients with severe, acute respiratory failure undergoing venovenous extracorporeal membrane oxygenation (VV-ECMO), the optimal strategy for mechanical ventilation is unclear.Our objective was to describe ventilation practices used in centers registered with the Extracorporeal Life Support Organization (ELSO).We conducted an international cross-sectional survey of medical directors and ECMO program coordinators from all ELSO-registered centers. The survey was distributed using a commercial website that collected information on center characteristics, the presence of a mechanical ventilator protocol, ventilator settings, and weaning practices. E-mails were sent out to medical directors or coordinators at each ELSO center and their responses were pooled for analysis.We analyzed 141 (50%) individual responses from the 283 centers contacted across 28 countries. Only 27% of centers reported having an explicit mechanical ventilation protocol for ECMO patients. The majority of these centers (77%) reported "lung rest" to be the primary goal of mechanical ventilation, whereas 9% reported "lung recruitment" to be their ventilation strategy. A tidal volume of 6 ml/kg or less was targeted by 76% of respondents, and 58% targeted a positive end-expiratory pressure of 6-10 cm H2O while ventilating patients on VV-ECMO. Centers prioritized weaning VV-ECMO before mechanical ventilation.Although ventilation practices in patients supported by VV-ECMO vary across ELSO centers internationally, the majority of centers used a strategy that targeted lung-protective thresholds and prioritized weaning VV-ECMO over mechanical ventilation.