An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline.

Background: This document updates previously published Clinical Practice Guidelines for the management of patients with acute respiratory distress syndrome (ARDS), incorporating new evidence addressing the use of corticosteroids, venovenous extracorporeal membrane oxygenation, neuromuscular blocking agents, and positive end-expiratory pressure (PEEP). Methods: We summarized evidence addressing four "PICO questions" (patient, intervention, comparison, and outcome). A multidisciplinary panel with expertise in ARDS used the Grading of Recommendations, Assessment, Development, and Evaluation framework to develop clinical recommendations. Results: We suggest the use of: 1) corticosteroids for patients with ARDS (conditional recommendation, moderate certainty of evidence), 2) venovenous extracorporeal membrane oxygenation in selected patients with severe ARDS (conditional recommendation, low certainty of evidence), 3) neuromuscular blockers in patients with early severe ARDS (conditional recommendation, low certainty of evidence), and 4) higher PEEP without lung recruitment maneuvers as opposed to lower PEEP in patients with moderate to severe ARDS (conditional recommendation, low to moderate certainty), and 5) we recommend against using prolonged lung recruitment maneuvers in patients with moderate to severe ARDS (strong recommendation, moderate certainty). Conclusions: We provide updated evidence-based recommendations for the management of ARDS. Individual patient and illness characteristics should be factored into clinical decision making and implementation of these recommendations while additional evidence is generated from much-needed clinical trials.

Volatile anesthetics for lung- and diaphragm-protective sedation.

This review explores the complex interactions between sedation and invasive ventilation and examines the potential of volatile anesthetics for lung- and diaphragm-protective sedation. In the early stages of invasive ventilation, many critically ill patients experience insufficient respiratory drive and effort, leading to compromised diaphragm function. Compared with common intravenous agents, inhaled sedation with volatile anesthetics better preserves respiratory drive, potentially helping to maintain diaphragm function during prolonged periods of invasive ventilation. In turn, higher concentrations of volatile anesthetics reduce the size of spontaneously generated tidal volumes, potentially reducing lung stress and strain and with that the risk of self-inflicted lung injury. Taken together, inhaled sedation may allow titration of respiratory drive to maintain inspiratory efforts within lung- and diaphragm-protective ranges. Particularly in patients who are expected to require prolonged invasive ventilation, in whom the restoration of adequate but safe inspiratory effort is crucial for successful weaning, inhaled sedation represents an attractive option for lung- and diaphragm-protective sedation. A technical limitation is ventilatory dead space introduced by volatile anesthetic reflectors, although this impact is minimal and comparable to ventilation with heat and moisture exchangers. Further studies are imperative for a comprehensive understanding of the specific effects of inhaled sedation on respiratory drive and effort and, ultimately, how this translates into patient-centered outcomes in critically ill patients.

Respiratory drive heterogeneity associated with systemic inflammation and vascular permeability in acute respiratory distress syndrome.

BACKGROUND: In acute respiratory distress syndrome (ARDS), respiratory drive often differs among patients with similar clinical characteristics. Readily observable factors like acid-base state, oxygenation, mechanics, and sedation depth do not fully explain drive heterogeneity. This study evaluated the relationship of systemic inflammation and vascular permeability markers with respiratory drive and clinical outcomes in ARDS. METHODS: ARDS patients enrolled in the multicenter EPVent-2 trial with requisite data and plasma biomarkers were included. Neuromuscular blockade recipients were excluded. Respiratory drive was measured as PES0.1, the change in esophageal pressure during the first 0.1 s of inspiratory effort. Plasma angiopoietin-2, interleukin-6, and interleukin-8 were measured concomitantly, and 60-day clinical outcomes evaluated. RESULTS: 54.8% of 124 included patients had detectable respiratory drive (PES0.1 range of 0-5.1 cm H2O). Angiopoietin-2 and interleukin-8, but not interleukin-6, were associated with respiratory drive independently of acid-base, oxygenation, respiratory mechanics, and sedation depth. Sedation depth was not significantly associated with PES0.1 in an unadjusted model, or after adjusting for mechanics and chemoreceptor input. However, upon adding angiopoietin-2, interleukin-6, or interleukin-8 to models, lighter sedation was significantly associated with higher PES0.1. Risk of death was less with moderate drive (PES0.1 of 0.5-2.9 cm H2O) compared to either lower drive (hazard ratio 1.58, 95% CI 0.82-3.05) or higher drive (2.63, 95% CI 1.21-5.70) (p = 0.049). CONCLUSIONS: Among patients with ARDS, systemic inflammatory and vascular permeability markers were independently associated with higher respiratory drive. The heterogeneous response of respiratory drive to varying sedation depth may be explained in part by differences in inflammation and vascular permeability.

Mortality in Patients with Obesity and Acute Respiratory Distress Syndrome Receiving Extracorporeal Membrane Oxygenation: The Multicenter ECMObesity Study.

Rationale: Patients with obesity are at increased risk for developing acute respiratory distress syndrome (ARDS). Some centers consider obesity a relative contraindication to receiving extracorporeal membrane oxygenation (ECMO) support, despite growing implementation of ECMO for ARDS in the general population. Objectives: To investigate the association between obesity and mortality in patients with ARDS receiving ECMO. Methods: In this large, international, multicenter, retrospective cohort study, we evaluated the association of obesity, defined as body mass index ⩾ 30 kg/m2, with ICU mortality in patients receiving ECMO for ARDS by performing adjusted multivariable logistic regression and propensity score matching. Measurements and Main Results: Of 790 patients with ARDS receiving ECMO in our study, 320 had obesity. Of those, 24.1% died in the ICU, compared with 35.3% of patients without obesity (P < 0.001). In adjusted models, obesity was associated with lower ICU mortality (odds ratio, 0.63 [95% confidence interval, 0.43-0.93]; P = 0.018). Examined as a continuous variable, higher body mass index was associated with decreased ICU mortality in multivariable regression (odds ratio, 0.97 [95% confidence interval, 0.95-1.00]; P = 0.023). In propensity score matching of 199 patients with obesity to 199 patients without, patients with obesity had a lower probability of ICU death than those without (22.6% vs. 35.2%; P = 0.007). Conclusions: Among patients receiving ECMO for ARDS, those with obesity had lower ICU mortality than patients without obesity in multivariable and propensity score matching analyses. Our findings support the notion that obesity should not be considered a general contraindication to ECMO.

Frequency of Screening and Spontaneous Breathing Trial Techniques: A Randomized Clinical Trial.

Importance: The optimal screening frequency and spontaneous breathing trial (SBT) technique to liberate adults from ventilators are unknown. Objective: To compare the effects of screening frequency (once-daily screening vs more frequent screening) and SBT technique (pressure-supported SBT with a pressure support level that was >0-≤8 cm H2O and a positive end-expiratory pressure [PEEP] level that was >0-≤5 cm H2O vs T-piece SBT) on the time to successful extubation. Design, Setting, and Participants: Randomized clinical trial with a 2 × 2 factorial design including critically ill adults who were receiving invasive mechanical ventilation for at least 24 hours, who were capable of initiating spontaneous breaths or triggering ventilators, and who were receiving a fractional concentration of inspired oxygen that was 70% or less and a PEEP level of 12 cm H2O or less. Recruitment was between January 2018 and February 2022 at 23 intensive care units in North America; last follow-up occurred October 18, 2022. Interventions: Participants were enrolled early to enable protocolized screening (more frequent vs once daily) to identify the earliest that patients met criteria to undergo pressure-supported or T-piece SBT lasting 30 to 120 minutes. Main Outcome and Measures: Time to successful extubation (time when unsupported, spontaneous breathing began and was sustained for ≥48 hours after extubation). Results: Of 797 patients (198 in the once-daily screening and pressure-supported SBT group, 204 in once-daily screening and T-piece SBT, 195 in more frequent screening and pressure-supported SBT, and 200 in more frequent screening and T-piece SBT), the mean age was 62.4 (SD, 18.4) years and 472 (59.2%) were men. There were no statistically significant differences by screening frequency (hazard ratio [HR], 0.88 [95% CI, 0.76-1.03]; P = .12) or by SBT technique (HR, 1.06 [95% CI, 0.91-1.23]; P = .45). The median time to successful extubation was 2.0 days (95% CI, 1.7-2.7) for once-daily screening and pressure-supported SBT, 3.1 days (95% CI, 2.7-4.8) for once-daily screening and T-piece SBT, 3.9 days (95% CI, 2.9-4.7) for more frequent screening and pressure-supported SBT, and 2.9 days (95% CI, 2.0-3.1) for more frequent screening and T-piece SBT. An unexpected interaction between screening frequency and SBT technique required pairwise contrasts that revealed more frequent screening (vs once-daily screening) and pressure-supported SBT increased the time to successful extubation (HR, 0.70 [95% CI, 0.50-0.96]; P = .02). Once-daily screening and pressure-supported SBT (vs T-piece SBT) did not reduce the time to successful extubation (HR, 1.30 [95% CI, 0.98-1.70]; P = .08). Conclusions and Relevance: Among critically ill adults who received invasive mechanical ventilation for more than 24 hours, screening frequency (once-daily vs more frequent screening) and SBT technique (pressure-supported vs T-piece SBT) did not change the time to successful extubation. However, an unexpected and statistically significant interaction was identified; protocolized more frequent screening combined with pressure-supported SBTs increased the time to first successful extubation. Trial Registration: ClinicalTrials.gov Identifiers: NCT02399267 and NCT02969226.

Risks and Benefits of Ultra-Lung-Protective Invasive Mechanical Ventilation Strategies with a Focus on Extracorporeal Support.

Lung-protective ventilation strategies are the current standard of care for patients with acute respiratory distress syndrome in an effort to provide adequate ventilatory requirements while minimizing ventilator-induced lung injury. Some patients may benefit from ultra-lung-protective ventilation, a strategy that achieves lower airway pressures and Vt than the current standard. Specific physiological parameters beyond severity of hypoxemia, such as driving pressure and respiratory system elastance, may be predictive of those most likely to benefit. Because application of ultra-lung-protective ventilation is often limited by respiratory acidosis, extracorporeal membrane oxygenation or extracorporeal carbon dioxide removal, which remove carbon dioxide from blood, is an attractive option. These strategies are associated with hematological complications, especially when applied at low blood-flow rates with devices designed for higher blood flows, and a recent large randomized controlled trial failed to show a benefit from an extracorporeal carbon dioxide removal-facilitated ultra-lung-protective ventilation strategy. Only in patients with very severe forms of acute respiratory distress syndrome has the use of an ultra-lung-protective ventilation strategy-accomplished with extracorporeal membrane oxygenation-been suggested to have a favorable risk-to-benefit profile. In this critical care perspective, we address key areas of controversy related to ultra-lung-protective ventilation, including the trade-offs between minimizing ventilator-induced lung injury and the risks from strategies to achieve this added protection. In addition, we suggest which patients might benefit most from an ultra-lung-protective strategy and propose areas of future research.

Association of Positive End-Expiratory Pressure and Lung Recruitment Selection Strategies with Mortality in Acute Respiratory Distress Syndrome: A Systematic Review and Network Meta-analysis.

Rationale: The most beneficial positive end-expiratory pressure (PEEP) selection strategy in patients with acute respiratory distress syndrome (ARDS) is unknown, and current practice is variable. Objectives: To compare the relative effects of different PEEP selection strategies on mortality in adults with moderate to severe ARDS. Methods: We conducted a network meta-analysis using a Bayesian framework. Certainty of evidence was evaluated using grading of recommendations assessment, development and evaluation methodology. Measurements and Main Results: We included 18 randomized trials (4,646 participants). Compared with a lower PEEP strategy, the posterior probability of mortality benefit from a higher PEEP without lung recruitment maneuver (LRM) strategy was 99% (risk ratio [RR], 0.77; 95% credible interval [CrI], 0.60-0.96, high certainty), the posterior probability of benefit of the esophageal pressure-guided strategy was 87% (RR, 0.77; 95% CrI, 0.48-1.22, moderate certainty), the posterior probability of benefit of a higher PEEP with brief LRM strategy was 96% (RR, 0.83; 95% CrI, 0.67-1.02, moderate certainty), and the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 77% (RR, 1.06; 95% CrI, 0.89-1.22, low certainty). Compared with a higher PEEP without LRM strategy, the posterior probability of increased mortality from a higher PEEP with prolonged LRM strategy was 99% (RR, 1.37; 95% CrI, 1.04-1.81, moderate certainty). Conclusions: In patients with moderate to severe ARDS, higher PEEP without LRM is associated with a lower risk of death than lower PEEP. A higher PEEP with prolonged LRM strategy is associated with increased risk of death when compared with higher PEEP without LRM.

Effect of Esophageal Pressure-guided Positive End-Expiratory Pressure on Survival from Acute Respiratory Distress Syndrome: A Risk-based and Mechanistic Reanalysis of the EPVent-2 Trial.

Rationale: In acute respiratory distress syndrome (ARDS), the effect of positive end-expiratory pressure (PEEP) may depend on the extent to which multiorgan dysfunction contributes to risk of death, and the precision with which PEEP is titrated to attenuate atelectrauma without exacerbating overdistension. Objectives: To evaluate whether multiorgan dysfunction and lung mechanics modified treatment effect in the EPVent-2 (Esophageal Pressure-guided Ventilation 2) trial, a multicenter trial of esophageal pressure (Pes)-guided PEEP versus empirical high PEEP in moderate to severe ARDS. Methods: This post hoc reanalysis of the EPVent-2 trial evaluated for heterogeneity of treatment effect on mortality by baseline multiorgan dysfunction, determined via Acute Physiology and Chronic Health Evaluation II (APACHE-II). It also evaluated whether PEEP titrated to end-expiratory transpulmonary pressure near 0 cm H2O was associated with survival. Measurements and Main Results: All 200 trial participants were included. Treatment effect on 60-day mortality differed by multiorgan dysfunction severity (P = 0.03 for interaction). Pes-guided PEEP was associated with lower mortality among patients with APACHE-II less than the median value (hazard ratio, 0.43; 95% confidence interval, 0.20-0.92) and may have had the opposite effect in patients with higher APACHE-II (hazard ratio, 1.69; 95% confidence interval, 0.93-3.05). Independent of treatment group or multiorgan dysfunction severity, mortality was lowest when PEEP titration achieved end-expiratory transpulmonary pressure near 0 cm H2O. Conclusions: The effect on survival of Pes-guided PEEP, compared with empirical high PEEP, differed by multiorgan dysfunction severity. Independent of multiorgan dysfunction, PEEP titrated to end-expiratory transpulmonary pressure closer to 0 cm H2O was associated with greater survival than more positive or negative values. These findings warrant prospective testing in a future trial.

Latent Class Analysis Reveals COVID-19-related Acute Respiratory Distress Syndrome Subgroups with Differential Responses to Corticosteroids.

Rationale: Two distinct subphenotypes have been identified in acute respiratory distress syndrome (ARDS), but the presence of subgroups in ARDS associated with coronavirus disease (COVID-19) is unknown. Objectives: To identify clinically relevant, novel subgroups in COVID-19-related ARDS and compare them with previously described ARDS subphenotypes. Methods: Eligible participants were adults with COVID-19 and ARDS at Columbia University Irving Medical Center. Latent class analysis was used to identify subgroups with baseline clinical, respiratory, and laboratory data serving as partitioning variables. A previously developed machine learning model was used to classify patients as the hypoinflammatory and hyperinflammatory subphenotypes. Baseline characteristics and clinical outcomes were compared between subgroups. Heterogeneity of treatment effect for corticosteroid use in subgroups was tested. Measurements and Main Results: From March 2, 2020, to April 30, 2020, 483 patients with COVID-19-related ARDS met study criteria. A two-class latent class analysis model best fit the population (P = 0.0075). Class 2 (23%) had higher proinflammatory markers, troponin, creatinine, and lactate, lower bicarbonate, and lower blood pressure than class 1 (77%). Ninety-day mortality was higher in class 2 versus class 1 (75% vs. 48%; P < 0.0001). Considerable overlap was observed between these subgroups and ARDS subphenotypes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RT-PCR cycle threshold was associated with mortality in the hypoinflammatory but not the hyperinflammatory phenotype. Heterogeneity of treatment effect to corticosteroids was observed (P = 0.0295), with improved mortality in the hyperinflammatory phenotype and worse mortality in the hypoinflammatory phenotype, with the caveat that corticosteroid treatment was not randomized. Conclusions: We identified two COVID-19-related ARDS subgroups with differential outcomes, similar to previously described ARDS subphenotypes. SARS-CoV-2 PCR cycle threshold had differential value for predicting mortality in the subphenotypes. The subphenotypes had differential treatment responses to corticosteroids.

Discordance Between Respiratory Drive and Sedation Depth in Critically Ill Patients Receiving Mechanical Ventilation.

OBJECTIVES: In mechanically ventilated patients, deep sedation is often assumed to induce "respirolysis," that is, lyse spontaneous respiratory effort, whereas light sedation is often assumed to preserve spontaneous effort. This study was conducted to determine validity of these common assumptions, evaluating the association of respiratory drive with sedation depth and ventilator-free days in acute respiratory failure. DESIGN: Prospective cohort study. SETTING: Patients were enrolled during 2 month-long periods in 2016-2017 from five ICUs representing medical, surgical, and cardiac specialties at a U.S. academic hospital. PATIENTS: Eligible patients were critically ill adults receiving invasive ventilation initiated no more than 36 hours before enrollment. Patients with neuromuscular disease compromising respiratory function or expiratory flow limitation were excluded. INTERVENTIONS: Respiratory drive was measured via P0.1, the change in airway pressure during a 0.1-second airway occlusion at initiation of patient inspiratory effort, every 12 ± 3 hours for 3 days. Sedation depth was evaluated via the Richmond Agitation-Sedation Scale. Analyses evaluated the association of P0.1 with Richmond Agitation-Sedation Scale (primary outcome) and ventilator-free days. MEASUREMENTS AND MAIN RESULTS: Fifty-six patients undergoing 197 bedside evaluations across five ICUs were included. P0.1 ranged between 0 and 13.3 cm H2O (median [interquartile range], 0.1 cm H2O [0.0-1.3 cm H2O]). P0.1 was not significantly correlated with the Richmond Agitation-Sedation Scale (RSpearman, 0.02; 95% CI, -0.12 to 0.16; p = 0.80). Considering P0.1 terciles (range less than 0.2, 0.2-1.0, and greater than 1.0 cm H2O), patients in the middle tercile had significantly more ventilator-free days than the lowest tercile (incidence rate ratio, 0.78; 95% CI, 0.65-0.93; p < 0.01) or highest tercile (incidence rate ratio, 0.58; 95% CI, 0.48-0.70; p < 0.01). CONCLUSIONS: Sedation depth is not a reliable marker of respiratory drive during critical illness. Respiratory drive can be low, moderate, or high across the range of routinely targeted sedation depth.

Promises and challenges of personalized medicine to guide ARDS therapy.

Identifying new effective treatments for the acute respiratory distress syndrome (ARDS), including COVID-19 ARDS, remains a challenge. The field of ARDS investigation is moving increasingly toward innovative approaches such as the personalization of therapy to biological and clinical sub-phenotypes. Additionally, there is growing recognition of the importance of the global context to identify effective ARDS treatments. This review highlights emerging opportunities and continued challenges for personalizing therapy for ARDS, from identifying treatable traits to innovative clinical trial design and recognition of patient-level factors as the field of critical care investigation moves forward into the twenty-first century.

Mechanical Ventilation for Acute Respiratory Distress Syndrome during Extracorporeal Life Support. Research and Practice.

Ventilator-induced lung injury remains a key contributor to the morbidity and mortality of acute respiratory distress syndrome (ARDS). Efforts to minimize this injury are typically limited by the need to preserve adequate gas exchange. In the most severe forms of the syndrome, extracorporeal life support is increasingly being deployed for severe hypoxemia or hypercapnic acidosis refractory to conventional ventilator management strategies. Data from a recent randomized controlled trial, a post hoc analysis of that trial, a meta-analysis, and a large international multicenter observational study suggest that extracorporeal life support, when combined with lower Vt and airway pressures than the current standard of care, may improve outcomes compared with conventional management in patients with the most severe forms of ARDS. These findings raise important questions not only about the optimal ventilation strategies for patients receiving extracorporeal support but also regarding how various mechanisms of lung injury in ARDS may potentially be mitigated by ultra-lung-protective ventilation strategies when gas exchange is sufficiently managed with the extracorporeal circuit. Additional studies are needed to more precisely delineate the best strategies for optimizing invasive mechanical ventilation in this patient population.

Lung- and Diaphragm-Protective Ventilation.

Mechanical ventilation can cause acute diaphragm atrophy and injury, and this is associated with poor clinical outcomes. Although the importance and impact of lung-protective ventilation is widely appreciated and well established, the concept of diaphragm-protective ventilation has recently emerged as a potential complementary therapeutic strategy. This Perspective, developed from discussions at a meeting of international experts convened by PLUG (the Pleural Pressure Working Group) of the European Society of Intensive Care Medicine, outlines a conceptual framework for an integrated lung- and diaphragm-protective approach to mechanical ventilation on the basis of growing evidence about mechanisms of injury. We propose targets for diaphragm protection based on respiratory effort and patient-ventilator synchrony. The potential for conflict between diaphragm protection and lung protection under certain conditions is discussed; we emphasize that when conflicts arise, lung protection must be prioritized over diaphragm protection. Monitoring respiratory effort is essential to concomitantly protect both the diaphragm and the lung during mechanical ventilation. To implement lung- and diaphragm-protective ventilation, new approaches to monitoring, to setting the ventilator, and to titrating sedation will be required. Adjunctive interventions, including extracorporeal life support techniques, phrenic nerve stimulation, and clinical decision-support systems, may also play an important role in selected patients in the future. Evaluating the clinical impact of this new paradigm will be challenging, owing to the complexity of the intervention. The concept of lung- and diaphragm-protective ventilation presents a new opportunity to potentially improve clinical outcomes for critically ill patients.

Alive and Ventilator Free: A Hierarchical, Composite Outcome for Clinical Trials in the Acute Respiratory Distress Syndrome.

OBJECTIVES: Survival from acute respiratory distress syndrome is improving, and outcomes beyond mortality may be important for testing new treatments. The "ventilator-free days" score, is an established composite that equates ventilation on day 28 to death. A hierarchical outcome treating death as a worse than prolonged ventilation would enhance face validity, but performance characteristics and reporting of such an outcome are unknown. We therefore evaluated the performance of a novel hierarchical composite endpoint, the Alive and Ventilator Free score. DESIGN: Using data from four Acute Respiratory Distress Syndrome Network clinical trials, we compared Alive and Ventilator Free to the ventilator-free days score. Alive and Ventilator Free compares each patient with every other patient in a win-lose-tie for each comparison. Duration of mechanical ventilation is only compared if both patients survived. We evaluated power of Alive and Ventilator Free versus ventilator-free days score under various circumstances. SETTING: ICUs within the Acute Respiratory Distress Syndrome Network. PATIENTS: Individuals enrolled in four Acute Respiratory Distress Syndrome Network trials. INTERVENTIONS: None for this analysis. MEASUREMENTS AND MAIN RESULTS: Within the four trials (n = 2,410 patients), Alive and Ventilator Free and ventilator-free days score had similar power, with Alive and Ventilator Free slightly more powerful when a mortality difference was present, and ventilator-free days score slightly more powerful with a difference in duration of mechanical ventilation. Alive and Ventilator Free less often found in favor of treatments that increased mortality and increased days free of ventilation among survivors. CONCLUSIONS: A hierarchical composite endpoint, Alive and Ventilator Free, preserves statistical power while improving face validity. Alive and Ventilator Free is less prone to favor a treatment with discordant effects on survival and days free of ventilation. This general approach can support complex outcome hierarchies with multiple constituent outcomes. Approaches to interpretation of differences in Alive and Ventilator Free are also presented.

Powering Bias and Clinically Important Treatment Effects in Randomized Trials of Critical Illness.

OBJECTIVES: Recurring issues in clinical trial design may bias results toward the null, yielding findings inconclusive for treatment effects. This study evaluated for powering bias among high-impact critical care trials and the associated risk of masking clinically important treatment effects. DESIGN, SETTING, AND PATIENTS: Secondary analysis of multicenter randomized trials of critically ill adults in which mortality was the main endpoint. Trials were eligible for inclusion if published between 2008 and 2018 in leading journals. Analyses evaluated for accuracy of estimated control group mortality, adaptive sample size strategy, plausibility of predicted treatment effect, and results relative to the minimal clinically important difference. The main outcome was the mortality risk difference at the study-specific follow-up interval. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 101 included trials, 12 met statistical significance for their main endpoint, five for increased intervention-associated mortality. Most trials (77.3%) overestimated control group mortality in power calculations (observed minus predicted difference, -6.7% ± 9.8%; p < 0.01). Due to this misestimation of control group mortality, in 14 trials, the intervention would have had to prevent at least half of all deaths to achieve the hypothesized treatment effect. Seven trials prespecified adaptive sample size strategies that might have mitigated this issue. The observed risk difference for mortality fell within 5% of predicted in 20 trials, of which 16 did not reach statistical significance. Half of trials (47.0%) were powered for an absolute risk reduction greater than or equal to 10%, but this effect size was observed in only three trials with a statistically significant treatment benefit. Most trials (67.3%) could not exclude clinically important treatment benefit or harm. CONCLUSIONS: The design of most high-impact critical care trials biased results toward the null by overestimating control group mortality and powering for unrealistic treatment effects. Clinically important treatment effects often cannot be excluded.

Lung protection in acute respiratory distress syndrome: what should we target?

PURPOSE OF REVIEW: Most clinical trials of lung-protective ventilation have tested one-size-fits-all strategies with mixed results. Data are lacking on how best to tailor mechanical ventilation to patient-specific risk of lung injury. RECENT FINDINGS: Risk of ventilation-induced lung injury is determined by biological predisposition to biophysical lung injury and physical mechanical perturbations that concentrate stress and strain regionally within the lung. Recent investigations have identified molecular subphenotypes classified as hyperinflammatory and hypoinflammatory acute respiratory distress syndrome (ARDS), which may have dissimilar risk for ventilation-induced lung injury. Mechanically, gravity-dependent atelectasis has long been recognized to decrease total aerated lung volume available for tidal ventilation, a concept termed the 'ARDS baby lung'. Recent studies have demonstrated that the aerated baby lung also has nonuniform stress/strain distribution, with potentially injurious forces concentrated in zones of heterogeneity where aerated alveoli are adjacent to flooded or atelectatic alveoli. The preponderance of evidence also indicates that current standard-of-care tidal volume management is not universally protective in ARDS. When considering escalation of lung-protective interventions, potential benefits of the intervention should be weighed against tradeoffs of accompanying cointerventions required, for example, deeper sedation or neuromuscular blockade. A precision medicine approach to lung-protection would weigh. SUMMARY: A precision medicine approach to lung-protective ventilation requires weighing four key factors in each patient: biological predisposition to biophysical lung injury, mechanical predisposition to biophysical injury accounting for spatial mechanical heterogeneity within the lung, anticipated benefits of escalating lung-protective interventions, and potential unintended adverse effects of mandatory cointerventions.

Equipoise in Appropriate Initial Volume Resuscitation for Patients in Septic Shock With Heart Failure: Results of a Multicenter Clinician Survey.

PURPOSE: International clinical practice guidelines call for initial volume resuscitation of at least 30 mL/kg body weight for patients with sepsis-induced hypotension or shock. Although not considered in the guidelines, preexisting cardiac dysfunction may be an important factor clinicians weigh in deciding the quantity of volume resuscitation for patients with septic shock. METHODS: We conducted a multicenter survey of clinicians who routinely treat patients with sepsis to evaluate their beliefs, behaviors, knowledge, and perceived structural barriers regarding initial volume resuscitation for patients with sepsis and concomitant heart failure with reduced ejection fraction (HFrEF) <40%. Initial volume resuscitation preferences were captured as ordinal values, and additional testing for volume resuscitation preferences was performed using McNemar and Wilcoxon signed rank tests as indicated. Univariable logistic regression models were used to identify significant predictors of ≥30 mL/kg fluid administration. RESULTS: A total of 317 clinicians at 9 US hospitals completed the survey (response rate 47.3%). Most respondents were specialists in either internal medicine or emergency medicine. Substantial heterogeneity was found regarding sepsis resuscitation preferences for patients with concomitant HFrEF. The belief that patients with septic shock and HFrEF should be exempt from current sepsis bundle initiatives was shared by 39.4% of respondents. A minimum fluid challenge of ∼30 mL/kg or more was deemed appropriate in septic shock by only 56.4% of respondents for patients with concomitant HFrEF, compared to 89.1% of respondents for patients without HFrEF (P < .01). Emergency medicine physicians were most likely to feel that <30 mL/kg was most appropriate in patients with septic shock and HFrEF. CONCLUSIONS: Clinical equipoise exists regarding initial volume resuscitation for patients with sepsis-induced hypotension or shock and concomitant HFrEF. Future studies and clinical practice guidelines should explicitly address resuscitation in this subpopulation.

Physiologic Analysis and Clinical Performance of the Ventilatory Ratio in Acute Respiratory Distress Syndrome.

RATIONALE: Pulmonary dead space fraction (Vd/Vt) is an independent predictor of mortality in acute respiratory distress syndrome (ARDS). Yet, it is seldom used in practice. The ventilatory ratio is a simple bedside index that can be calculated using routinely measured respiratory variables and is a measure of impaired ventilation. Ventilatory ratio is defined as [minute ventilation (ml/min) × PaCO2 (mm Hg)]/(predicted body weight × 100 × 37.5). OBJECTIVES: To determine the relation of ventilatory ratio with Vd/Vt in ARDS. METHODS: First, in a single-center, prospective observational study of ARDS, we tested the association of Vd/Vt with ventilatory ratio. With in-hospital mortality as the primary outcome and ventilator-free days as the secondary outcome, we tested the role of ventilatory ratio as an outcome predictor. The findings from this study were further verified in secondary analyses of two NHLBI ARDS Network randomized controlled trials. MEASUREMENTS AND MAIN RESULTS: Ventilatory ratio positively correlated with Vd/Vt. Ordinal groups of ventilatory ratio had significantly higher Vd/Vt. Ventilatory ratio was independently associated with increased risk of mortality after adjusting for PaO2/FiO2, and positive end-expiratory pressure (odds ratio, 1.51; P = 0.024) and after adjusting for Acute Physiologic Assessment and Chronic Health Evaluation II score (odds ratio, 1.59; P = 0.04). These findings were further replicated in secondary analyses of two separate NHLBI randomized controlled trials. CONCLUSIONS: Ventilatory ratio correlates well with Vd/Vt in ARDS, and higher values at baseline are associated with increased risk of adverse outcomes. These results are promising for the use of ventilatory ratio as a simple bedside index of impaired ventilation in ARDS.

Female Physician Leadership During Cardiopulmonary Resuscitation Is Associated With Improved Patient Outcomes.

OBJECTIVES: A recently published simulation study suggested that women are inferior leaders of cardiopulmonary resuscitation efforts. The aim of this study was to compare female and male code leaders in regard to cardiopulmonary resuscitation outcomes in a real-world clinical setting. DESIGN: Retrospective cohort review. SETTING: Two academic, urban hospitals in San Diego, California. SUBJECTS: One-thousand eighty-two adult inpatients who suffered cardiac arrest and underwent cardiopulmonary resuscitation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed whether physician code leader gender was independently associated with sustained return of spontaneous circulation and survival to discharge and with markers of quality cardiopulmonary resuscitation. Of all arrests, 327 (30.1%) were run by female physician code leaders with 251 (76.8%) obtaining return of spontaneous circulation, and 122 (37.3%) surviving to discharge. Male physicians ran 757 codes obtaining return of spontaneous circulation in 543 (71.7%) with 226 (29.9%) surviving to discharge. When adjusting for variables, female physician code leader gender was independently associated with a higher likelihood of return of spontaneous circulation (odds ratio, 1.36; 95% CI, 1.01-1.85; p = 0.049) and survival to discharge (odds ratio, 1.53; 95% CI, 1.15-2.02; p < 0.01). Additionally, the odds ratio for survival to discharge was 1.62 (95% CI, 1.13-2.34; p < 0.01) for female physicians with a female code nurse when compared with male physician code leaders paired with a female code nurse. Gender of code leader was not associated with cardiopulmonary resuscitation quality. CONCLUSIONS: In contrast to data derived from a simulated setting with medical students, real life female physician leadership of cardiopulmonary resuscitation is not associated with inferior outcomes. Appropriately, trained physicians can lead high-quality cardiopulmonary resuscitation irrespective of gender.