Comparison of venovenous extracorporeal membrane oxygenation, prone position and supine mechanical ventilation for severely hypoxemic acute respiratory distress syndrome: a network meta-analysis.

PURPOSE: Severe acute respiratory distress syndrome (ARDS) with PaO2/FiO2 < 80 mmHg is a life-threatening condition. The optimal management strategy is unclear. The aim of this meta-analysis was to compare the effects of low tidal volumes (Vt), moderate Vt, prone ventilation, and venovenous extracorporeal membrane oxygenation (VV-ECMO) on mortality in severe ARDS. METHODS: We performed a frequentist network meta-analysis of randomised controlled trials (RCTs) with participants who had severe ARDS and met eligibility criteria for VV-ECMO or had PaO2/FiO2 < 80 mmHg. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to discern the relative effect of interventions on mortality and the certainty of the evidence. RESULTS: Ten RCTs including 812 participants with severe ARDS were eligible. VV-ECMO reduces mortality compared to low Vt (risk ratio [RR] 0.77, 95% confidence interval [CI] 0.59-0.99, moderate certainty) and compared to moderate Vt (RR 0.75, 95% CI 0.57-0.98, low certainty). Prone ventilation reduces mortality compared to moderate Vt (RR 0.78, 95% CI 0.66-0.93, high certainty) and compared to low Vt (RR 0.81, 95% CI 0.63-1.02, moderate certainty). We found no difference in the network comparison of VV-ECMO compared to prone ventilation (RR 0.95, 95% CI 0.72-1.26), but inferences were based solely on indirect comparisons with very low certainty due to very wide confidence intervals. CONCLUSIONS: In adults with ARDS and severe hypoxia, both VV-ECMO (low to moderate certainty evidence) and prone ventilation (moderate to high certainty evidence) improve mortality relative to low and moderate Vt strategies. The impact of VV-ECMO versus prone ventilation remains uncertain.

Designing a Bayesian adaptive clinical trial to evaluate novel mechanical ventilation strategies in acute respiratory failure using integrated nested Laplace approximations.

BACKGROUND: Adaptive trials usually require simulations to determine values for design parameters, demonstrate error rates, and establish the sample size. We designed a Bayesian adaptive trial comparing ventilation strategies for patients with acute hypoxemic respiratory failure using simulations. The complexity of the analysis would usually require computationally expensive Markov Chain Monte Carlo methods but this barrier to simulation was overcome using the Integrated Nested Laplace Approximations (INLA) algorithm to provide fast, approximate Bayesian inference. METHODS: We simulated two-arm Bayesian adaptive trials with equal randomization that stratified participants into two disease severity states. The analysis used a proportional odds model, fit using INLA. Trials were stopped based on pre-specified posterior probability thresholds for superiority or futility, separately for each state. We calculated the type I error and power across 64 scenarios that varied the probability thresholds and the initial minimum sample size before commencing adaptive analyses. Two designs that maintained a type I error below 5%, a power above 80%, and a feasible mean sample size were evaluated further to determine the optimal design. RESULTS: Power generally increased as the initial sample size and the futility threshold increased. The chosen design had an initial recruitment of 500 and a superiority threshold of 0.9925, and futility threshold of 0.95. It maintained high power and was likely to reach a conclusion before exceeding a feasible sample size. CONCLUSIONS: We designed a Bayesian adaptive trial to evaluate novel strategies for ventilation using the INLA algorithm to efficiently evaluate a wide range of designs through simulation.

Dyssynchronous diaphragm contractions impair diaphragm function in mechanically ventilated patients.

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).

A New Global Definition of Acute Respiratory Distress Syndrome.

Background: Since publication of the 2012 Berlin definition of acute respiratory distress syndrome (ARDS), several developments have supported the need for an expansion of the definition, including the use of high-flow nasal oxygen, the expansion of the use of pulse oximetry in place of arterial blood gases, the use of ultrasound for chest imaging, and the need for applicability in resource-limited settings. Methods: A consensus conference of 32 critical care ARDS experts was convened, had six virtual meetings (June 2021 to March 2022), and subsequently obtained input from members of several critical care societies. The goal was to develop a definition that would 1) identify patients with the currently accepted conceptual framework for ARDS, 2) facilitate rapid ARDS diagnosis for clinical care and research, 3) be applicable in resource-limited settings, 4) be useful for testing specific therapies, and 5) be practical for communication to patients and caregivers. Results: The committee made four main recommendations: 1) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min; 2) use PaO2:FiO2 ⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry SpO2:FiO2 ⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify hypoxemia; 3) retain bilateral opacities for imaging criteria but add ultrasound as an imaging modality, especially in resource-limited areas; and 4) in resource-limited settings, do not require positive end-expiratory pressure, oxygen flow rate, or specific respiratory support devices. Conclusions: We propose a new global definition of ARDS that builds on the Berlin definition. The recommendations also identify areas for future research, including the need for prospective assessments of the feasibility, reliability, and prognostic validity of the proposed global definition.

Overnight staffing in Canadian neonatal and pediatric intensive care units.

Aim: Infants and children who require specialized medical attention are admitted to neonatal and pediatric intensive care units (ICUs) for continuous and closely supervised care. Overnight in-house physician coverage is frequently considered the ideal staffing model. It remains unclear how often this is achieved in both pediatric and neonatal ICUs in Canada. The aim of this study is to describe overnight in-house physician staffing in Canadian pediatric and level-3 neonatal ICUs (NICUs) in the pre-COVID-19 era. Methods: A national cross-sectional survey was conducted in 34 NICUs and 19 pediatric ICUs (PICUs). ICU directors or their delegates completed a 29-question survey describing overnight staffing by resident physicians, fellow physicians, nurse practitioners, and attending physicians. A comparative analysis was conducted between ICUs with and without in-house physicians. Results: We obtained responses from all 34 NICUs and 19 PICUs included in this study. A total of 44 ICUs (83%) with in-house overnight physician coverage provided advanced technologies, such as extracorporeal life support, and included all ICUs that catered to patients with cardiac, transplant, or trauma conditions. Residents provided the majority of overnight coverage, followed by the Critical Care Medicine fellows. An attending physician was in-house overnight in eight (15%) out of the 53 ICUs, seven of which were NICUs. Residents participating in rotations in the ICU would often have rotation durations of less than 6 weeks and were often responsible for providing care during shifts lasting 20-24 h. Conclusion: Most PICUs and level-3 NICUs in Canada have a dedicated in-house physician overnight. These physicians are mainly residents or fellows, but a notable variation exists in this arrangement. The potential effects on patient outcomes, resident learning, and physician satisfaction remain unclear and warrant further investigation.

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.

ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies.

The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients' representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research.

Liberation From Venovenous Extracorporeal Membrane Oxygenation for Respiratory Failure: A Scoping Review.

BACKGROUND: Safe and timely liberation from venovenous extracorporeal membrane oxygenation (ECMO) would be expected to reduce the duration of ECMO, the risk of complications, and costs. However, how to liberate patients from venovenous ECMO effectively remains understudied. RESEARCH QUESTION: What is the current state of the evidence on liberation from venovenous ECMO? STUDY DESIGN AND METHODS: We systematically searched for relevant publications on liberation from venovenous ECMO in Medline and EMBASE. Citations were included if the manuscripts provided any of the following: criteria for readiness for liberation, a liberation protocol, or a definition of successful decannulation or decannulation failure. We included randomized trials, observational trials, narrative reviews, guidelines, editorials, and commentaries. We excluded single case reports and citations where the full text was unavailable. RESULTS: We screened 1,467 citations to identify 39 key publications on liberation from venovenous ECMO. We then summarized the data into five main topics: current strategies used for liberation, criteria used to define readiness for liberation, conducting liberation trials, criteria used to proceed with decannulation, and parameters used to predict decannulation outcomes. INTERPRETATION: Practices on liberation from venovenous ECMO are heterogeneous and are influenced strongly by clinician preference. Additional research on liberation thresholds is needed to define optimal liberation strategies and to close existing knowledge gaps in essential topics on liberation from venovenous ECMO.

Outcomes of patients with respiratory failure declined for extracorporeal membrane oxygenation: a prospective observational study.

PURPOSE: Descriptive information on referral patterns and short-term outcomes of patients with respiratory failure declined for extracorporeal membrane oxygenation (ECMO) is lacking. METHODS: We conducted a prospective single-centre observational cohort study of ECMO referrals to Toronto General Hospital (receiving hospital) for severe respiratory failure (COVID-19 and non-COVID-19), between 1 December 2019 and 30 November 2020. Data related to the referral, the referral decision, and reasons for refusal were collected. Reasons for refusal were grouped into three mutually exclusive categories selected a priori: "too sick now," "too sick before," and "not sick enough." In declined referrals, referring physicians were surveyed to collect patient outcome on day 7 after the referral. The primary study endpoints were referral outcome (accepted/declined) and patient outcome (alive/deceased). RESULTS: A total of 193 referrals were included; 73% were declined for transfer. Referral outcome was influenced by age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.95 to 0.96; P < 0.01) and involvement of other members of the ECMO team in the discussion (OR, 4.42; 95% CI, 1.28 to 15.2; P < 0.01). Patient outcomes were missing in 46 (24%) referrals (inability to locate the referring physician or the referring physician being unable to recall the outcome). Using available data (95 declined and 52 accepted referrals; n = 147), survival to day 7 was 49% for declined referrals (35% for patients deemed "too sick now," 53% for "too sick before," 100% for "not sick enough," and 50% for reason for refusal not reported) and 98% for transferred patients. Sensitivity analysis setting missing outcomes to directional extreme values retained robustness of survival probabilities. CONCLUSION: Nearly half of the patients declined for ECMO consideration were alive on day 7. More information on patient trajectory and long-term outcomes in declined referrals is needed to refine selection criteria.

RéSUMé: OBJECTIF: On manque d'informations descriptives sur les schémas de références et les devenirs à court terme des patient·es atteint·es d'insuffisance respiratoire n'ayant pas pu recevoir une oxygénation par membrane extracorporelle (ECMO). MéTHODE: Nous avons réalisé une étude de cohorte observationnelle prospective monocentrique sur les références vers l'ECMO à l'Hôpital général de Toronto (hôpital d'accueil) pour insuffisance respiratoire grave (COVID-19 et non-COVID-19), entre le 1er décembre 2019 et le 30 novembre 2020. Les données relatives à la référence, à la décision de référence et aux motifs du refus ont été recueillies. Les motifs de refus ont été regroupés en trois catégories mutuellement exclusives sélectionnées a priori : « Trop malade maintenant ¼, « Trop malade avant ¼ et « Pas assez malade ¼. En ce qui concerne les références refusées, un sondage envoyé aux médecins traitant·es avait pour objectif de recueillir les devenirs des patient·es le jour 7 suivant la référence. Les critères d'évaluation principaux de l'étude étaient le résultat de la référence (accepté/refusé) et le devenir des patient·es (vivant·e/décédé·e). RéSULTATS: Au total, 193 références ont été incluses; le transfert a été refusé dans 73 % des cas. L'acceptation ou le refus de la référence était influencé par l'âge (rapport de cotes [RC], 0,97; intervalle de confiance [IC] à 95 %, 0,95 à 0,96; P < 0,01) et la participation d'autres membres de l'équipe ECMO à la discussion (RC, 4,42; IC 95 %, 1,28 à 15,2; P < 0,01). Les devenirs des patient·es étaient manquants pour 46 (24 %) des personnes référées (incapacité de localiser les médecins traitant·es ou incapacité des médecins de se souvenir du devenir). À l'aide des données disponibles (95 références refusées et 52 références acceptées; n = 147), la survie jusqu'au jour 7 était de 49 % pour les références refusées (35 % pour la patientèle jugée « trop malade maintenant ¼, 53 % pour celle « trop malade avant ¼, 100 % pour celle « pas assez malade ¼ et 50 % pour les cas où la raison du refus n'était pas déclarée) et 98 % pour les patient·es transféré·es. L'analyse de sensibilité établissant les résultats manquants à des valeurs extrêmes directionnelles a conservé la robustesse des probabilités de survie. CONCLUSION: Près de la moitié des patient·es pour lesquel·les un traitement sous ECMO a été refusé étaient en vie au jour 7. Davantage d'informations concernant la trajectoire et les devenirs à long terme des patient·es refusé·es sont nécessaires pour parfaire les critères de sélection.

Limiting Dynamic Driving Pressure in Patients Requiring Mechanical Ventilation.

OBJECTIVES: Previous studies reported an association between higher driving pressure (∆P) and increased mortality for different groups of mechanically ventilated patients. However, it remained unclear if sustained intervention on ∆P, in addition to traditional lung-protective ventilation, improves outcomes. We investigated if ventilation strategies limiting daily static or dynamic ∆P reduce mortality compared with usual care in adult patients requiring greater than or equal to 24 hours of mechanical ventilation. DESIGN: For this comparative effectiveness study, we emulated pragmatic clinical trials using data from the Toronto Intensive Care Observational Registry recorded between April 2014 and August 2021. The per-protocol effect of the interventions was estimated using the parametric g-formula, a method that controls for baseline and time-varying confounding, as well as for competing events in the analysis of longitudinal exposures. SETTING: Nine ICUs from seven University of Toronto-affiliated hospitals. PATIENTS: Adult patients (≥18 yr) requiring greater than or equal to 24 hours of mechanical ventilation. INTERVENTIONS: Receipt of a ventilation strategy that limited either daily static or dynamic ∆P less than or equal to 15 cm H 2 O compared with usual care. MEASUREMENTS AND MAIN RESULTS: Among the 12,865 eligible patients, 4,468 of (35%) were ventilated with dynamic ∆P greater than 15 cm H 2 O at baseline. Mortality under usual care was 20.1% (95% CI, 19.4-20.9%). Limiting daily dynamic ∆P less than or equal to 15 cm H 2 O in addition to traditional lung-protective ventilation reduced adherence-adjusted mortality to 18.1% (95% CI, 17.5-18.9%) (risk ratio, 0.90; 95% CI, 0.89-0.92). In further analyses, this effect was most pronounced for early and sustained interventions. Static ∆P at baseline were recorded in only 2,473 patients but similar effects were observed. Conversely, strict interventions on tidal volumes or peak inspiratory pressures, irrespective of ∆P, did not reduce mortality compared with usual care. CONCLUSIONS: Limiting either static or dynamic ∆P can further reduce the mortality of patients requiring mechanical ventilation.

Epinephrine in Out-of-Hospital Cardiac Arrest: A Network Meta-analysis and Subgroup Analyses of Shockable and Nonshockable Rhythms.

BACKGROUND: Epinephrine is the most commonly used drug in out-of-hospital cardiac arrest (OHCA) resuscitation, but evidence supporting its efficacy is mixed. RESEARCH QUESTION: What are the comparative efficacy and safety of standard dose epinephrine, high-dose epinephrine, epinephrine plus vasopressin, and placebo or no treatment in improving outcomes after OHCA? STUDY DESIGN AND METHODS: In this systematic review and network meta-analysis of randomized controlled trials, we searched six databases from inception through June 2022 for randomized controlled trials evaluating epinephrine use during OHCA resuscitation. We performed frequentist random-effects network meta-analysis and present ORs and 95% CIs. We used the the Grading of Recommendations, Assessment, Development, and Evaluation approach to rate the certainty of evidence. Outcomes included return of spontaneous circulation (ROSC), survival to hospital admission, survival to discharge, and survival with good functional outcome. RESULTS: We included 18 trials (21,594 patients). Compared with placebo or no treatment, high-dose epinephrine (OR, 4.27; 95% CI, 3.68-4.97), standard-dose epinephrine (OR, 3.69; 95% CI, 3.32-4.10), and epinephrine plus vasopressin (OR, 3.54; 95% CI, 2.94-4.26) all increased ROSC. High-dose epinephrine (OR, 3.53; 95% CI, 2.97-4.20), standard-dose epinephrine (OR, 3.00; 95% CI, 2.66-3.38), and epinephrine plus vasopressin (OR, 2.79; 95% CI, 2.27-3.44) all increased survival to hospital admission as compared with placebo or no treatment. However, none of these agents may increase survival to discharge or survival with good functional outcome as compared with placebo or no treatment. Compared with placebo or no treatment, standard-dose epinephrine improved survival to discharge among patients with nonshockable rhythm (OR, 2.10; 95% CI, 1.21-3.63), but not in those with shockable rhythm (OR, 0.85; 95% CI, 0.39-1.85). INTERPRETATION: Use of standard-dose epinephrine, high-dose epinephrine, and epinephrine plus vasopressin increases ROSC and survival to hospital admission, but may not improve survival to discharge or functional outcome. Standard-dose epinephrine improved survival to discharge among patients with nonshockable rhythm, but not those with shockable rhythm. TRIAL REGISTRY: Center for Open Science: https://osf.io/arxwq.