BACKGROUND: We evaluated the influence of different partial carbon dioxide pressure (PaCO2) levels on organ perfusion in patients with respiratory failure receiving pressure-support ventilation with veno-venous extracorporeal membrane oxygenation (V-V ECMO).
METHODS: In this twelve patients prospective study, ECMO gas-flow was decreased from baseline (PaCO2 < 40 mmHg) until PaCO2 increased by 5-10 mmHg (High-CO2 phase). Resistance indices of gut, spleen, and snuffbox artery, the peripheral perfusion index (PPI), and heart rate variability were measured at baseline and High-CO2 phase.
RESULTS: When PaCO2 increased from 36 (36-37) mmHg at baseline to 42 (41-43) mmHg in the High-CO2 phase (p < 0.001), PPI decreased significantly (p = 0.026). The snuffbox artery (p = 0.022), superior mesenteric artery (p = 0.042), and spleen (p = 0.012) resistance indices increased significantly. The root mean square of successive differences (RMSSD) decreased from 19.5(18.1-22.7) to 15.9(14.4-18.6) ms (p = 0.034), and the ratio of low-frequency to high-frequency components(LF/HF) increased from 0.47 ± 0.23 to 0.70 ± 0.38 (p = 0.013).
CONCLUSIONS: High PaCO2 might cause decreased peripheral tissue and visceral organ perfusion through autonomic nervous system in patients with respiratory failure undergoing PSV with V-V ECMO.

BACKGROUND: Acute respiratory failure is a life-threatening condition frequently found in the emergency department. High-flow nasal oxygen (HFNO) is increasingly used in emergency departments for patients with hypoxaemic acute respiratory failure. However, despite the increasing number of studies, its potential advantages regarding the need for therapeutic escalation and mortality have not been precisely evaluated. Our objective is to compare conventional oxygen therapy to HFNO when they are initiated during the first hour following the patient\'s arrival at the emergency department, with the hypothesis that HFNO would reduce the need for ventilatory therapy escalation.
METHODS: This is a multicentric, prospective, open and randomised superiority study. 500 inpatients will be randomised (1:1) to receive conventional oxygen therapy or HNFO. The primary outcome is a failure in the oxygen therapy defined as the need for a therapeutic escalation within 4 hours after therapy initiation.
BACKGROUND: The study has been submitted and approved by the Comité de Protection des Personnes Nord Ouest IV (20 October 2020). As required, a notification was sent to the Agence nationale de sécurité du médicament et des produits de santé (22 October 2020). The research results will be published in peer-reviewed publications and presented at international conferences.
BACKGROUND: NCT04607967.

BACKGROUND: The ratio (E/Ea) of mitral Doppler inflow velocity to annular tissue Doppler wave velocity by transthoracic echocardiography and diaphragmatic excursion (DE) by diaphragm ultrasound have been confirmed to predict extubation outcomes. However, few studies focused on the predicting value of E/Ea and DE at different positions during a spontaneous breathing trial (SBT), as well as the effects of △E/Ea and △DE (changes in E/Ea and DE during a SBT).
METHODS: This study was a reanalysis of the data of 60 difficult-to-wean patients in a previous study published in 2017. All eligible participants were organized into respiratory failure (RF) group and extubation success (ES) group within 48 h after extubation, or re-intubation (RI) group and non-intubation (NI) group within 1 week after extubation. The risk factors for respiratory failure and re-intubation including E/Ea and △E/Ea, DE and △DE at different positions were analyzed by multivariate logistic regression, respectively. The receiver operating characteristic (ROC) curves of E/Ea (septal, lateral, average) and DE (right, left, average) were compared with each other, respectively.
RESULTS: Of the 60 patients, 29 cases developed respiratory failure within 48 h, and 14 of those cases required re-intubation within 1 week. Multivariate logistic regression showed that E/Ea were all associated with respiratory failure, while only DE (right) and DE (average) after SBT were related to re-intubation. There were no statistic differences among the ROC curves of E/Ea at different positions, nor between the ROC curves of DE. No statistical differences were shown in △E/Ea between RF and ES groups, while △DE (average) was remarkably higher in NI group than that in RI group. However, multivariate logistic regression analysis showed that △DE (average) was not associated with re-intubation.
CONCLUSIONS: E/Ea at different positions during a SBT could predict postextubation respiratory failure with no statistical differences among them. Likewise, only DE (right) and DE (average) after SBT might predict re-intubation with no statistical differences between each other.

OBJECTIVE: Patients with acute respiratory failure often require mechanical ventilation to reduce the work of breathing and improve gas exchange; however, this may exacerbate lung injury. Protective ventilation strategies, characterized by low tidal volumes (≤ 8mL/kg of predicted body weight) and limited plateau pressure below 30cmH2O, have shown improved outcomes in patients with acute respiratory distress syndrome. However, in the transition to spontaneous ventilation, it can be challenging to maintain tidal volume within protective levels, and it is unclear whether low tidal volumes during spontaneous ventilation impact patient outcomes. We developed a study protocol to estimate the prevalence of low tidal volume ventilation in the first 24 hours of spontaneous ventilation in patients with hypoxemic acute respiratory failure and its association with ventilator-free days and survival.
METHODS: We designed a multicenter, multinational, cohort study with a 28-day follow-up that will include patients with acute respiratory failure, defined as a partial oxygen pressure/fraction of inspired oxygen ratio < 300mmHg, in transition to spontaneous ventilation in intensive care units in Latin America.
RESULTS: We plan to include 422 patients in ten countries. The primary outcomes are the prevalence of low tidal volume in the first 24 hours of spontaneous ventilation and ventilator-free days on day 28. The secondary outcomes are intensive care unit and hospital mortality, incidence of asynchrony and return to controlled ventilation and sedation.
CONCLUSIONS: In this study, we will assess the prevalence of low tidal volume during spontaneous ventilation and its association with clinical outcomes, which can inform clinical practice and future clinical trials.

The aim of this study is to determine if extended-release, bioabsorbable, subcutaneous naltrexone (NTX) implants can mitigate respiratory depression after an intravenous injection (IV) of fentanyl. Six different BIOabsorbable Polymeric Implant Naltrexone (BIOPIN) formulations, comprising combinations of Poly-d,l-Lactic Acid (PDLLA) and/or Polycaprolactone (PCL-1 or PCL-2), were used to create subcutaneous implants. Both placebo and naltrexone implants were implanted subcutaneously in male dogs. The active naltrexone implants consisted of two doses, 644 mg and 1288 mg. A challenge with IV fentanyl was performed in 33 male dogs at 97-100 days after implantation. Following the administration of a 30 μg/kg intravenous fentanyl dose, the placebo cohort manifested a swift and profound respiratory depression with a ~50% reduction in their pre-dose respiratory rate (RR). The BIOPIN NTX-implanted dogs were exposed to escalating doses of intravenous fentanyl (30 μg/kg, 60 μg/kg, 90 μg/kg, and 120 μg/kg). In contrast, the dogs implanted with the BIOPIN naltrexone implants tolerated doses up to 60 μg/kg without significant respiratory depression (<50%) but had severe respiratory depression with fentanyl doses of 90 μg/kg and especially at 120 μg/kg. Bioabsorbable, extended-release BIOPIN naltrexone implants are effective in mitigating fentanyl-induced respiratory depression in male canines at about 3 months after implantation. This technology may also have potential for mitigating fentanyl-induced respiratory depression in humans.

BACKGROUND: Noninvasive ventilation (NIV) has been the cornerstone for managing acute exacerbations of COPD (AECOPD) with hypercapnic respiratory failure. Nasal high flow (NHF) oxygen therapy has emerged as a potential alternative, offering a more tolerable modality with promising outcomes. The aim of the present study was to evaluate whether NHF respiratory support is noninferior to NIV with respect to treatment failure, in patients with mild-to-moderate hypercapnic AECOPD.
METHODS: In this multi-center, randomized, noninferiority trial, 105 patients with AECOPD and respiratory failure type II were enrolled. Participants were randomly assigned to receive either NHF therapy or NIV. The primary endpoint was the frequency of treatment failure, defined as the need for intubation and invasive mechanical ventilation or a switch to the alternative treatment group. Secondary endpoints included changes in respiratory parameters, patient comfort indicators, and the occurrence of complications.
RESULTS: The findings revealed no significant difference in the primary outcome between the groups, with a treatment failure rate of 19.6 % (10 out of 51) in the NHF group and 14.8 % (8 out of 54) in the NIV group. Interestingly, NHF users reported significantly lower levels of dyspnea and discomfort at multiple follow-up points. Despite the differences in patient comfort, respiratory parameters such as respiratory rate, arterial blood gases, and use of accessory muscles of respiration showed no significant disparities between the groups throughout the study period.
CONCLUSIONS: NHF therapy was similar to NIV in preventing treatment failure among patients with hypercapnic AECOPD, offering a viable alternative with enhanced comfort.
BACKGROUND: The study was prospectively registered in ClinicalTrials.gov (Identifier: NCT03466385) on March 15, 2018.

OBJECTIVE: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is an integral part of the management algorithm of patients with severe respiratory failure refractory to evidence-based conventional treatments. Right ventricular injury (RVI) pertaining to abnormalities in the dimensions and/or function of the right ventricle (RV) in the context of VV-ECMO significantly influences mortality. However, in the absence of a universally accepted RVI definition and evidence-based guidance for the management of RVI in this very high-risk patient cohort, variations in clinical practice continue to exist.
METHODS: Following a systematic search of the literature, an international Steering Committee consisting of eight healthcare professionals involved in the management of patients receiving ECMO identified domains and knowledge gaps pertaining to RVI definition and management where the evidence is limited or ambiguous. Using a Delphi process, an international panel of 52 Experts developed Expert position statements in those areas. The process also conferred RV-centric overarching open questions for future research. Consensus was defined as achieved when 70% or more of the Experts agreed or disagreed on a Likert-scale statement or when 80% or more of the Experts agreed on a particular option in multiple-choice questions.
RESULTS: The Delphi process was conducted through four rounds and consensus was achieved on 31 (89%) of 35 statements from which 24 Expert position statements were derived. Expert position statements provided recommendations for RVI nomenclature in the setting of VV-ECMO, a multi-modal diagnostic approach to RVI, the timing and parameters of diagnostic echocardiography, and VV-ECMO settings during RVI assessment and management. Consensus was not reached on RV-protective driving pressure thresholds or the effect of prone positioning on patient-centric outcomes.
CONCLUSIONS: The proposed definition of RVI in the context of VV-ECMO needs to be validated through a systematic aggregation of data across studies. Until further evidence emerges, the Expert position statements can guide informed decision-making in the management of these patients.

OBJECTIVE: Awake prone positioning has been reported to reduce endotracheal intubation in patients with coronavirus disease 2019 (COVID-19)-related acute hypoxemic respiratory failure (AHRF). However, it is still unclear whether using the awake prone positioning for longer periods can further improve outcomes.
METHODS: In this randomized, open-label clinical trial conducted at 12 hospitals in China, non-intubated patients with COVID-19-related AHRF were randomly assigned to prolonged awake prone positioning (target > 12 h daily for 7 days) or standard care with a shorter period of awake prone positioning. The primary outcome was endotracheal intubation within 28 days after randomization. The key secondary outcomes included mortality and adverse events.
RESULTS: In total, 409 patients were enrolled and randomly assigned to prolonged awake prone positioning (n = 205) or standard care (n = 204). In the first 7 days after randomization, the median duration of prone positioning was 12 h/d (interquartile range [IQR] 12-14 h/d) in the prolonged awake prone positioning group vs. 5 h/d (IQR 2-8 h/d) in the standard care group. In the intention-to-treat analysis, intubation occurred in 35 (17%) patients assigned to prolonged awake prone positioning and in 56 (27%) patients assigned to standard care (relative risk 0.62 [95% confidence interval (CI) 0.42-0.9]). The hazard ratio (HR) for intubation was 0.56 (0.37-0.86), and for mortality was 0.63 (0.42-0.96) for prolonged awake prone positioning versus standard care, within 28 days. The incidence of pre-specified adverse events was low and similar in both groups.
CONCLUSIONS: Prolonged awake prone positioning of patients with COVID-19-related AHRF reduces the intubation rate without significant harm. These results support prolonged awake prone positioning of patients with COVID-19-related AHRF.

BACKGROUND: Remimazolam is not only associated with a lower incidence of respiratory depression than propofol but also in itself has the risk of respiratory depression.
OBJECTIVE: We investigated respiratory depression following remimazolam infusion, targeting different effect-site concentrations using target-controlled infusion.
METHODS: A prospective, double-blind, randomised controlled study.
METHODS: Tertiary hospital, Suwon, South Korea, from April 2022 to November 2022.
METHODS: One hundred and seven patients scheduled for general anaesthesia were randomised into three groups targeting remimazolam effect-site concentrations of 500 (RMZ-500) ( n  = 36), 1000 (RMZ-1000) ( n  = 35) and 1500 ng ml -1 (RMZ-1500) ( n  = 36).
METHODS: Remimazolam was solely infused for 10 min according to target effect-site concentrations. According to the degree of SpO 2 decrease, oxygen desaturations were managed with the following respiratory supports: jaw-thrust for SpO 2 less than 97%, 100% oxygen delivery for SpO 2 less than 93% and assisted ventilation for SpO 2 less than 90%.
METHODS: The incidence of each respiratory support, along with respiratory variables (at baseline, 5 min and 10 min after remimazolam infusion) and loss of consciousness were observed for 10 min after remimazolam target-controlled infusion.
RESULTS: Both RMZ-1000 and RMZ-1500 required more frequent respiratory support than RMZ-500 (both P  < 0.001), with nearly identical frequencies between RMZ-1000 and RMZ-1500. In terms of respiratory support, the incidence of assisted ventilation was significantly lower in RMZ-500 (2.8%) than RMZ-1000 (48.6%) and RMZ-1500 (50%) ( P  < 0.001). RMZ-1000 and RMZ-1500 achieved loss of consciousness in all patients; RMZ-500 only achieved loss of consciousness in 86.1% of patients ( P  = 0.010). In patients who maintained spontaneous respiration, tidal volume decreased by 41 to 48% and respiratory rate increased by 118 to 158% at 5 and 10 min, significantly compared to baseline in all groups ( P  < 0.001).
CONCLUSIONS: Remimazolam infusion, like that of other benzodiazepines, led to respiratory depression, which was more prominent at higher target effect-site concentrations. Therefore, appropriate countermeasures should be developed to prevent oxygen desaturation.
BACKGROUND: CRIS ( https://cris.nih.go.kr ), identifier: KCT0006952.

OBJECTIVE: Although noninvasive ventilation (NIV) may reduce reintubation in patients with acute hypoxemic respiratory failure following abdominal surgery, this strategy has not been specifically assessed in patients with obesity.
METHODS: We conducted a post hoc analysis of a multicenter randomized controlled trial comparing NIV delivered via facial mask to standard oxygen therapy among patients with obesity and acute hypoxemic respiratory failure within 7 days after abdominal surgery. The primary outcome was reintubation within 7 days. Secondary outcomes were invasive ventilation-free days at day 30, intensive care unit (ICU)-acquired pneumonia and 30-day survival.
RESULTS: Among 293 patients with hypoxemic respiratory failure following abdominal surgery, 76 (26%) patients had obesity and were included in the intention-to-treat analysis. Reintubation rate was significantly lower with NIV (13/42, 31%) than with standard oxygen therapy (19/34, 56%) within 7 days (absolute difference: - 25%, 95% confidence interval (CI) - 49 to - 1%, p = 0.03). NIV was associated with significantly more invasive ventilation-free days compared with standard oxygen therapy (27.1 ± 8.6 vs 22.7 ± 11.1 days; p = 0.02), while fewer patients developed ICU-acquired pneumonia (1/42, 2% vs 6/34, 18%; p = 0.04). The 30-day survival was 98% in the NIV group (41/42) versus 85% in the standard oxygen therapy (p = 0.08). In patients with body mass index (BMI) < 30 kg/m2, no significant difference was observed between NIV (36/105, 34%) and standard oxygen therapy (47/109, 43%, p = 0.03). An interaction test showed no statistically significant difference between the two subsets (BMI ≥ 30 kg/m2 and BMI < 30 kg/m2).
CONCLUSIONS: Among patients with obesity and hypoxemic respiratory failure following abdominal surgery, use of NIV compared with standard oxygen therapy reduced the risk of reintubation within 7 days, contrary to patients without obesity. However, no interaction was found according to the presence of obesity or not, suggesting either a lack of power to conclude in the non-obese subgroup despite existing differences, or that the statistical difference found in the overall sample was driven by a large effect in the obese subsets.