Lung Recruitment Assessed by Electrical Impedance Tomography (RECRUIT): A Multicenter Study of COVID-19 Acute Respiratory Distress Syndrome.

Rationale: Defining lung recruitability is needed for safe positive end-expiratory pressure (PEEP) selection in mechanically ventilated patients. However, there is no simple bedside method including both assessment of recruitability and risks of overdistension as well as personalized PEEP titration. Objectives: To describe the range of recruitability using electrical impedance tomography (EIT), effects of PEEP on recruitability, respiratory mechanics and gas exchange, and a method to select optimal EIT-based PEEP. Methods: This is the analysis of patients with coronavirus disease (COVID-19) from an ongoing multicenter prospective physiological study including patients with moderate-severe acute respiratory distress syndrome of different causes. EIT, ventilator data, hemodynamics, and arterial blood gases were obtained during PEEP titration maneuvers. EIT-based optimal PEEP was defined as the crossing point of the overdistension and collapse curves during a decremental PEEP trial. Recruitability was defined as the amount of modifiable collapse when increasing PEEP from 6 to 24 cm H2O (ΔCollapse24-6). Patients were classified as low, medium, or high recruiters on the basis of tertiles of ΔCollapse24-6. Measurements and Main Results: In 108 patients with COVID-19, recruitability varied from 0.3% to 66.9% and was unrelated to acute respiratory distress syndrome severity. Median EIT-based PEEP differed between groups: 10 versus 13.5 versus 15.5 cm H2O for low versus medium versus high recruitability (P < 0.05). This approach assigned a different PEEP level from the highest compliance approach in 81% of patients. The protocol was well tolerated; in four patients, the PEEP level did not reach 24 cm H2O because of hemodynamic instability. Conclusions: Recruitability varies widely among patients with COVID-19. EIT allows personalizing PEEP setting as a compromise between recruitability and overdistension. Clinical trial registered with www.clinicaltrials.gov (NCT04460859).

Clinical risk factors for increased respiratory drive in intubated hypoxemic patients.

BACKGROUND: There is very limited evidence identifying factors that increase respiratory drive in hypoxemic intubated patients. Most physiological determinants of respiratory drive cannot be directly assessed at the bedside (e.g., neural inputs from chemo- or mechano-receptors), but clinical risk factors commonly measured in intubated patients could be correlated with increased drive. We aimed to identify clinical risk factors independently associated with increased respiratory drive in intubated hypoxemic patients. METHODS: We analyzed the physiological dataset from a multicenter trial on intubated hypoxemic patients on pressure support (PS). Patients with simultaneous assessment of the inspiratory drop in airway pressure at 0.1-s during an occlusion (P0.1) and risk factors for increased respiratory drive on day 1 were included. We evaluated the independent correlation of the following clinical risk factors for increased drive with P0.1: severity of lung injury (unilateral vs. bilateral pulmonary infiltrates, PaO2/FiO2, ventilatory ratio); arterial blood gases (PaO2, PaCO2 and pHa); sedation (RASS score and drug type); SOFA score; arterial lactate; ventilation settings (PEEP, level of PS, addition of sigh breaths). RESULTS: Two-hundred seventeen patients were included. Clinical risk factors independently correlated with higher P0.1 were bilateral infiltrates (increase ratio [IR] 1.233, 95%CI 1.047-1.451, p = 0.012); lower PaO2/FiO2 (IR 0.998, 95%CI 0.997-0.999, p = 0.004); higher ventilatory ratio (IR 1.538, 95%CI 1.267-1.867, p < 0.001); lower pHa (IR 0.104, 95%CI 0.024-0.464, p = 0.003). Higher PEEP was correlated with lower P0.1 (IR 0.951, 95%CI 0.921-0.982, p = 0.002), while sedation depth and drugs were not associated with P0.1. CONCLUSIONS: Independent clinical risk factors for higher respiratory drive in intubated hypoxemic patients include the extent of lung edema and of ventilation-perfusion mismatch, lower pHa, and lower PEEP, while sedation strategy does not affect drive. These data underline the multifactorial nature of increased respiratory drive.

High-Flow Versus VenturiMask Oxygen Therapy to Prevent Reintubation in Hypoxemic Patients after Extubation: A Multicenter Randomized Clinical Trial.

Rationale: When compared with VenturiMask after extubation, high-flow nasal oxygen provides physiological advantages. Objectives: To establish whether high-flow oxygen prevents endotracheal reintubation in hypoxemic patients after extubation, compared with VenturiMask. Methods: In this multicenter randomized trial, 494 patients exhibiting PaO2:FiO2 ratio ⩽ 300 mm Hg after extubation were randomly assigned to receive high-flow or VenturiMask oxygen, with the possibility to apply rescue noninvasive ventilation before reintubation. High-flow use in the VenturiMask group was not permitted. Measurements and Main Results: The primary outcome was the rate of reintubation within 72 hours according to predefined criteria, which were validated a posteriori by an independent adjudication committee. Main secondary outcomes included reintubation rate at 28 days and the need for rescue noninvasive ventilation according to predefined criteria. After intubation criteria validation (n = 492 patients), 32 patients (13%) in the high-flow group and 27 patients (11%) in the VenturiMask group required reintubation at 72 hours (unadjusted odds ratio, 1.26 [95% confidence interval (CI), 0.70-2.26]; P = 0.49). At 28 days, the rate of reintubation was 21% in the high-flow group and 23% in the VenturiMask group (adjusted hazard ratio, 0.89 [95% CI, 0.60-1.31]; P = 0.55). The need for rescue noninvasive ventilation was significantly lower in the high-flow group than in the VenturiMask group: at 72 hours, 8% versus 17% (adjusted hazard ratio, 0.39 [95% CI, 0.22-0.71]; P = 0.002) and at 28 days, 12% versus 21% (adjusted hazard ratio, 0.52 [95% CI, 0.32-0.83]; P = 0.007). Conclusions: Reintubation rate did not significantly differ between patients treated with VenturiMask or high-flow oxygen after extubation. High-flow oxygen yielded less frequent use of rescue noninvasive ventilation. Clinical trial registered with www.clinicaltrials.gov (NCT02107183).

The PROMIZING trial enrollment algorithm for early identification of patients ready for unassisted breathing.

BACKGROUND: Liberating patients from mechanical ventilation (MV) requires a systematic approach. In the context of a clinical trial, we developed a simple algorithm to identify patients who tolerate assisted ventilation but still require ongoing MV to be randomized. We report on the use of this algorithm to screen potential trial participants for enrollment and subsequent randomization in the Proportional Assist Ventilation for Minimizing the Duration of MV (PROMIZING) study. METHODS: The algorithm included five steps: enrollment criteria, pressure support ventilation (PSV) tolerance trial, weaning criteria, continuous positive airway pressure (CPAP) tolerance trial (0 cmH2O during 2 min) and spontaneous breathing trial (SBT): on fraction of inspired oxygen (FiO2) 40% for 30-120 min. Patients who failed the weaning criteria, CPAP Zero trial, or SBT were randomized. We describe the characteristics of patients who were initially enrolled, but passed all steps in the algorithm and consequently were not randomized. RESULTS: Among the 374 enrolled patients, 93 (25%) patients passed all five steps. At time of enrollment, most patients were on PSV (87%) with a mean (± standard deviation) FiO2 of 34 (± 6) %, PSV of 8.7 (± 2.9) cmH2O, and positive end-expiratory pressure of 6.1 (± 1.6) cmH2O. Minute ventilation was 9.0 (± 3.1) L/min with a respiratory rate of 17.4 (± 4.4) breaths/min. Patients were liberated from MV with a median [interquartile range] delay between initial screening and extubation of 5 [1-49] hours. Only 7 (8%) patients required reintubation. CONCLUSION: The trial algorithm permitted identification of 93 (25%) patients who were ready to extubate, while their clinicians predicted a duration of ventilation higher than 24 h.

Non-invasive oxygenation support in acutely hypoxemic COVID-19 patients admitted to the ICU: a multicenter observational retrospective study.

BACKGROUND: Non-invasive oxygenation strategies have a prominent role in the treatment of acute hypoxemic respiratory failure during the coronavirus disease 2019 (COVID-19). While the efficacy of these therapies has been studied in hospitalized patients with COVID-19, the clinical outcomes associated with oxygen masks, high-flow oxygen therapy by nasal cannula and non-invasive mechanical ventilation in critically ill intensive care unit (ICU) patients remain unclear. METHODS: In this retrospective study, we used the best of nine covariate balancing algorithms on all baseline covariates in critically ill COVID-19 patients supported with > 10 L of supplemental oxygen at one of the 26 participating ICUs in Catalonia, Spain, between March 14 and April 15, 2020. RESULTS: Of the 1093 non-invasively oxygenated patients at ICU admission treated with one of the three stand-alone non-invasive oxygenation strategies, 897 (82%) required endotracheal intubation and 310 (28%) died during the ICU stay. High-flow oxygen therapy by nasal cannula (n = 439) and non-invasive mechanical ventilation (n = 101) were associated with a lower rate of endotracheal intubation (70% and 88%, respectively) than oxygen masks (n = 553 and 91% intubated), p < 0.001. Compared to oxygen masks, high-flow oxygen therapy by nasal cannula was associated with lower ICU mortality (hazard ratio 0.75 [95% CI 0.58-0.98), and the hazard ratio for ICU mortality was 1.21 [95% CI 0.80-1.83] for non-invasive mechanical ventilation. CONCLUSION: In critically ill COVID-19 ICU patients and, in the absence of conclusive data, high-flow oxygen therapy by nasal cannula may be the approach of choice as the primary non-invasive oxygenation support strategy.

Expert consensus statements for the management of COVID-19-related acute respiratory failure using a Delphi method.

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 (χ2) 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.

The central nervous system during lung injury and mechanical ventilation: a narrative review.

Mechanical ventilation induces a number of systemic responses for which the brain plays an essential role. During the last decade, substantial evidence has emerged showing that the brain modifies pulmonary responses to physical and biological stimuli by various mechanisms, including the modulation of neuroinflammatory reflexes and the onset of abnormal breathing patterns. Afferent signals and circulating factors from injured peripheral tissues, including the lung, can induce neuronal reprogramming, potentially contributing to neurocognitive dysfunction and psychological alterations seen in critically ill patients. These impairments are ubiquitous in the presence of positive pressure ventilation. This narrative review summarises current evidence of lung-brain crosstalk in patients receiving mechanical ventilation and describes the clinical implications of this crosstalk. Further, it proposes directions for future research ranging from identifying mechanisms of multiorgan failure to mitigating long-term sequelae after critical illness.

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.

High-Flow Nasal Cannula Compared With Conventional Oxygen Therapy or Noninvasive Ventilation Immediately Postextubation: A Systematic Review and Meta-Analysis.

OBJECTIVES: Reintubation after failed extubation is associated with increased mortality and longer hospital length of stay. Noninvasive oxygenation modalities may prevent reintubation. We conducted a systematic review and meta-analysis to determine the safety and efficacy of high-flow nasal cannula after extubation in critically ill adults. DATA SOURCES: We searched MEDLINE, EMBASE, and Web of Science. STUDY SELECTION: We included randomized controlled trials comparing high-flow nasal cannula to other noninvasive methods of oxygen delivery after extubation in critically ill adults. DATA EXTRACTION: We included the following outcomes: reintubation, postextubation respiratory failure, mortality, use of noninvasive ventilation, ICU and hospital length of stay, complications, and comfort. DATA SYNTHESIS: We included eight randomized controlled trials (n = 1,594 patients). Compared with conventional oxygen therapy, high-flow nasal cannula decreased reintubation (relative risk, 0.46; 95% CI, 0.30-0.70; moderate certainty) and postextubation respiratory failure (relative risk, 0.52; 95% CI, 0.30-0.91; very low certainty), but had no effect on mortality (relative risk, 0.93; 95% CI, 0.57-1.52; moderate certainty), or ICU length of stay (mean difference, 0.05 d fewer; 95% CI, 0.83 d fewer to 0.73 d more; high certainty). High-flow nasal cannula may decrease use of noninvasive ventilation (relative risk, 0.64; 95% CI, 0.34-1.22; moderate certainty) and hospital length of stay (mean difference, 0.98 d fewer; 95% CI, 2.16 d fewer to 0.21 d more; moderate certainty) compared with conventional oxygen therapy, however, certainty was limited by imprecision. Compared with noninvasive ventilation, high-flow nasal cannula had no effect on reintubation (relative risk, 1.16; 95% CI, 0.86-1.57; low certainty), mortality (relative risk, 1.12; 95% CI, 0.82-1.53; moderate certainty), or postextubation respiratory failure (relative risk, 0.82; 95% CI, 0.48-1.41; very low certainty). High-flow nasal cannula may reduce ICU length of stay (moderate certainty) and hospital length of stay (moderate certainty) compared with noninvasive ventilation. CONCLUSIONS: High-flow nasal cannula reduces reintubation compared with conventional oxygen therapy, but not compared with noninvasive ventilation after extubation.

Moderate Certainty Evidence Suggests the Use of High-Flow Nasal Cannula Does Not Decrease Hypoxia When Compared With Conventional Oxygen Therapy in the Peri-Intubation Period: Results of a Systematic Review and Meta-Analysis.

OBJECTIVE: The role of high-flow nasal cannula during and before intubation is unclear despite a number of randomized clinical trials. Our objective was to conduct a systematic review and meta-analysis examining the benefits of high-flow nasal cannula in the peri-intubation period. DATA SOURCES: We performed a comprehensive search of relevant databases (MEDLINE, EMBASE, and Web of Science). STUDY SELECTION: We included randomized clinical trials that compared high-flow nasal cannula to other noninvasive oxygen delivery systems in the peri-intubation period. DATA EXTRACTION: Our primary outcome was severe desaturation (defined as peripheral oxygen saturation reading < 80% during intubation). Secondary outcomes included peri-intubation complications, apneic time, PaO2 before and after intubation, PaCO2 after intubation, ICU length of stay, and short-term mortality. DATA SYNTHESIS: We included 10 randomized clinical trials (n = 1,017 patients). High-flow nasal cannula had no effect on the occurrence rate of peri-intubation hypoxemia (relative risk, 0.98; 95% CI, 0.68-1.42; 0.3% absolute risk reduction, moderate certainty), serious complications (relative risk, 0.87; 95% CI, 0.71-1.06), apneic time (mean difference, 10.3 s higher with high-flow nasal cannula; 95% CI, 11.0 s lower to 31.7 s higher), PaO2 measured after preoxygenation (mean difference, 3.6 mm Hg higher; 95% CI, 3.5 mm Hg lower to 10.7 mm Hg higher), or PaO2 measured after intubation (mean difference, 27.0 mm Hg higher; 95% CI, 13.2 mm Hg lower to 67.2 mm Hg higher), when compared with conventional oxygen therapy. There was also no effect on postintubation PaCO2, ICU length of stay, or 28-day mortality. CONCLUSIONS: We found moderate-to-low certainty evidence that the use of high-flow nasal cannula likely has no effect on severe desaturation, serious complications, apneic time, oxygenation, ICU length of stay, or overall survival when used in the peri-intubation period when compared with conventional oxygen therapy.

VENTILatOry strategies in patients with severe traumatic brain injury: the VENTILO Survey of the European Society of Intensive Care Medicine (ESICM).

BACKGROUND: Severe traumatic brain injury (TBI) patients often develop acute respiratory failure. Optimal ventilator strategies in this setting are not well established. We performed an international survey to investigate the practice in the ventilatory management of TBI patients with and without respiratory failure. METHODS: An electronic questionnaire, including 38 items and 3 different clinical scenarios [arterial partial pressure of oxygen (PaO2)/inspired fraction of oxygen (FiO2) > 300 (scenario 1), 150-300 (scenario 2), < 150 (scenario 3)], was available on the European Society of Intensive Care Medicine (ESICM) website between November 2018 and March 2019. The survey was endorsed by ESICM. RESULTS: There were 687 respondents [472 (69%) from Europe], mainly intensivists [328 (48%)] and anesthesiologists [206 (30%)]. A standard protocol for mechanical ventilation in TBI patients was utilized by 277 (40%) respondents and a specific weaning protocol by 198 (30%). The most common tidal volume (TV) applied was 6-8 ml/kg of predicted body weight (PBW) in scenarios 1-2 (72% PaO2/FIO2 > 300 and 61% PaO2/FiO2 150-300) and 4-6 ml/kg/PBW in scenario 3 (53% PaO2/FiO2 < 150). The most common level of highest positive end-expiratory pressure (PEEP) used was 15 cmH2O in patients with a PaO2/FiO2 ≤ 300 without intracranial hypertension (41% if PaO2/FiO2 150-300 and 50% if PaO2/FiO2 < 150) and 10 cmH2O in patients with intracranial hypertension (32% if PaO2/FiO2 150-300 and 33% if PaO2/FiO2 < 150). Regardless of the presence of intracranial hypertension, the most common carbon dioxide target remained 36-40 mmHg whereas the most common PaO2 target was 81-100 mmHg in all the 3 scenarios. The most frequent rescue strategies utilized in case of refractory respiratory failure despite conventional ventilator settings were neuromuscular blocking agents [406 (88%)], recruitment manoeuvres [319 (69%)] and prone position [292 (63%)]. CONCLUSIONS: Ventilatory management, targets and practice of adult severe TBI patients with and without respiratory failure are widely different among centres. These findings may be helpful to define future investigations in this topic.

Invasive Mechanical Ventilation in Chronic Obstructive Pulmonary Disease Exacerbations.

Chronic obstructive pulmonary disease (COPD) continues to be an important cause of morbidity, mortality, and health care costs worldwide. Although there exist some heterogeneity between patients, the course of COPD is characterized by recurrent acute exacerbations, which are among the most common causes of medical admission to hospital. Patients with frequent exacerbations have accelerated lung function decline, worse quality of life, and greater mortality. Therefore, interest is growing in assessing the effectiveness of interventions used to treat exacerbations. The present review summarizes the current evidence regarding the use of ventilatory management to treat COPD and the implementation of novel cost-effective strategies, such as high-flow oxygenation or extracorporeal carbon dioxide removal to improve clinical outcomes and functional recovery in this disease and to reduce the associated costs.

Intrathoracic Airway Closure Impacts CO2 Signal and Delivered Ventilation during Cardiopulmonary Resuscitation.

RATIONALE: End-tidal CO2 (EtCO2) is used to monitor cardiopulmonary resuscitation (CPR), but it can be affected by intrathoracic airway closure. Chest compressions induce oscillations in expired CO2, and this could reflect variable degrees of airway patency. OBJECTIVES: To understand the impact of airway closure during CPR, and the relationship between the capnogram shape, airway closure, and delivered ventilation. METHODS: This study had three parts: 1) a clinical study analyzing capnograms after intubation in patients with out-of-hospital cardiac arrest receiving continuous chest compressions, 2) a bench model, and 3) experiments with human cadavers. For 2 and 3, a constant CO2 flow was added in the lung to simulate CO2 production. Capnograms similar to clinical recordings were obtained and different ventilator settings tested. EtCO2 was compared with alveolar CO2 (bench). An airway opening index was used to quantify chest compression-induced expired CO2 oscillations in all three clinical and experimental settings. MEASUREMENTS AND MAIN RESULTS: A total of 89 patients were analyzed (mean age, 69 ± 15 yr; 23% female; 12% of hospital admission survival): capnograms exhibited various degrees of oscillations, quantified by the opening index. CO2 value varied considerably across oscillations related to consecutive chest compressions. In bench and cadavers, similar capnograms were reproduced with different degrees of airway closure. Differences in airway patency were associated with huge changes in delivered ventilation. The opening index and delivered ventilation increased with positive end-expiratory pressure, without affecting intrathoracic pressure. Maximal EtCO2 recorded between ventilator breaths reflected alveolar CO2 (bench). CONCLUSIONS: During chest compressions, intrathoracic airway patency greatly affects the delivered ventilation. The expired CO2 signal can reflect CPR effectiveness but is also dependent on airway patency. The maximal EtCO2 recorded between consecutive ventilator breaths best reflects alveolar CO2.

Medication errors in prescription and administration in critically ill patients.

AIM: To determine the prevalence and magnitude of medication errors and their association with patients' sociodemographic and clinical characteristics and nurses' work conditions. DESIGN: An observational, analytical, cross-sectional and ambispective study was conducted in critically ill adult patients. METHODS: Data concerning prescription errors were collected retrospectively from medical records and administration errors were identified through direct observation of nurses during drug administration. Those data were collected between April and July 2015. RESULTS: A total of 650 prescription errors were identified for 961 drugs in 90 patients (mean error 7[SD 4.1] per patient) and prevalence of 47.1% (95% CI 44-50). The most frequent error was omission of the prescribed medication. Intensive care unit stay was a risk factor associated with omission error (OR 2.14; 1.46-3.14: p < .01). A total of 294 administration errors were identified for 249 drugs in 52 patients (mean error 6 [SD 6.7] per patient) and prevalence of 73.5% (95% CI 68-79). The most frequent error was interruption during drug administration. Admission to the intensive care unit (OR 0.37; 0.21-0.66: p < .01), nurses' morning shift (OR 2.15; 1.10-4.18: p = .02) and workload perception (OR 3.64; 2.09-6.35: p < .01) were risk factors associated with interruption. CONCLUSIONS: Medication errors in prescription and administration were frequent. Timely detection of errors and promotion of a medication safety culture are necessary to reduce them and ensure the quality of care in critically ill patients. IMPACT: Medication errors occur frequently in the intensive care unit but are not always identified. Due to the vulnerability of seriously ill patients and the specialized care they require, an error can result in serious adverse events. The study shows that medication errors in prescription and administration are recurrent but preventable. These findings contribute to promote awareness in the proper use of medications and guarantee the quality of nursing care.

Effect of Intravenous Interferon ß-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) ß-1a may prevent the underlying event of vascular leakage. Objective: To determine the efficacy and adverse events of IFN-ß-1a in patients with moderate to severe ARDS. Design, Setting, and Participants: Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018. Interventions: Patients were randomized to receive an intravenous injection of 10 µg of IFN-ß-1a (144 patients) or placebo (152 patients) once daily for 6 days. Main Outcomes and Measures: The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error. Results: Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-ß-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-ß-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-ß-1a group and 33 [21.7%] in the placebo group). Conclusions and Relevance: Among adults with moderate or severe ARDS, intravenous IFN-ß-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-ß-1a in the management of ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02622724.

Efficacy and safety of lower versus higher CO2 extraction devices to allow ultraprotective ventilation: secondary analysis of the SUPERNOVA study.

Retrospective analysis of the SUPERNOVA trial exploring the hypothesis that efficacy and safety of extracorporeal carbon dioxide removal (ECCO2R) to facilitate reduction of tidal volume (VT) to 4 mL/kg in patients with acute respiratory distress syndrome (ARDS) may differ between systems with lower (area of membrane length 0.59 m2; blood flow 300-500 mL/min) and higher (membrane area 1.30 m2; blood flow between 800 and 1000 mL/min) CO2 extraction capacity. Ninety-five patients with moderate ARDS were included (33 patients treated with lower and 62 patients treated with higher CO2 extraction devices). We found that (1) VT of 4 mL/kg was reached by 55% and 64% of patients with the lower extraction versus 90% and 92% of patients with higher extraction devices at 8 and 24 hours from baseline, respectively (p<0.001), and (2) percentage of patients experiencing episodes of ECCO2R-related haemolysis and bleeding was higher with lower than with higher extraction devices (21% vs 6%, p=0.045% and 27% vs 6%, p=0.010, respectively). Although V T of 4 mL/kg could have been obtained with all devices, this was achieved frequently and with a lower rate of adverse events by devices with higher CO2 extraction capacity.

The Cost-Effectiveness of Interventions to Increase Utilization of Prone Positioning for Severe Acute Respiratory Distress Syndrome.

OBJECTIVES: Despite strong evidence supporting proning in acute respiratory distress syndrome, few eligible patients receive it. This study determines the cost-effectiveness of interventions to increase utilization of proning for severe acute respiratory distress syndrome. DESIGN: We created decision trees to model severe acute respiratory distress syndrome from ICU admission through death (societal perspective) and hospital discharge (hospital perspective). We assumed patients received low tidal volume ventilation. We used short-term outcome estimates from the PROSEVA trial and longitudinal cost and benefit data from cohort studies. In probabilistic sensitivity analyses, we used distributions for each input that included the fifth to 95th percentile of its CI. SETTING: ICUs that care for patients with acute respiratory distress syndrome. SUBJECTS: Patients with moderate to severe acute respiratory distress syndrome. INTERVENTIONS: The implementation of a hypothetical intervention to increase the appropriate utilization of prone positioning. MEASUREMENTS AND MAIN RESULTS: In the societal perspective model, an intervention that increased proning utilization from 16% to 65% yielded an additional 0.779 (95% CI, 0.088-1.714) quality-adjusted life years at an additional long-term cost of $31,156 (95% CI, -$158 to $92,179) (incremental cost-effectiveness ratio = $38,648 per quality-adjusted life year [95% CI, $1,695-$98,522]). If society was willing to pay $100,000 per quality-adjusted life year, any intervention costing less than $51,328 per patient with moderate to severe acute respiratory distress syndrome would represent good value. From a hospital perspective, the intervention yielded 0.072 (95% CI, 0.008-0.147) more survivals-to-discharge at a cost of $5,242 (95% CI, -$19,035 to $41,019) (incremental cost-effectiveness ratio = $44,615 per extra survival [95% CI, -$250,912 to $558,222]). If hospitals were willing to pay $100,000 per survival-to-discharge, any intervention costing less than $5,140 per patient would represent good value. CONCLUSIONS: Interventions that increase utilization of proning would be cost-effective from both societal and hospital perspectives under many plausible cost and benefit assumptions.

Fifty Years of Research in ARDS. Vt Selection in Acute Respiratory Distress Syndrome.

Mechanical ventilation (MV) is critical in the management of many patients with acute respiratory distress syndrome (ARDS). However, MV can also cause ventilator-induced lung injury (VILI). The selection of an appropriate Vt is an essential part of a lung-protective MV strategy. Since the publication of a large randomized clinical trial demonstrating the benefit of lower Vts, the use of Vts of 6 ml/kg predicted body weight (based on sex and height) has been recommended in clinical practice guidelines. However, the predicted body weight approach is imperfect in patients with ARDS because the amount of aerated lung varies considerably due to differences in inflammation, consolidation, flooding, and atelectasis. Better approaches to setting Vt may include limits on end-inspiratory transpulmonary pressure, lung strain, and driving pressure. The limits of lowering Vt have not yet been established, and some patients may benefit from Vts that are lower than those in current use. However, lowering Vts may result in respiratory acidosis. Tactics to reduce respiratory acidosis include reductions in ventilation circuit dead space, increases in respiratory rate, higher positive end-expiratory pressures in patients who recruit lung in response to positive end-expiratory pressure, recruitment maneuvers, and prone positioning. Mechanical adjuncts such as extracorporeal carbon dioxide removal may be useful to normalize pH and carbon dioxide levels, but further studies will be necessary to demonstrate benefit with this technology.