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Even though supplemental oxygen is used for the treatment of patients with hypoxemic respiratory failure, the most effective oxygenation targets are not known. In this randomized trial, a lower oxygenation target did not result in lower mortality than a higher target.

Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression. In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded. Fentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79% (69-89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21-76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68-132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001). Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl.

Background The association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure. Methods This was a prospective cohort study of children 2 weeks to 17 years of age with acute airways and/or parenchymal lung disease done in 22 pediatric intensive care units participating in the multi-center clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure ( RESTORE ). Plasma IL-8 levels were measured within 24 h of consent and 24 and 48 h later. DNA was purified from whole blood, and IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, were genotyped. Results Five hundred forty-nine patients were enrolled; 480 had blood sampling. Plasma IL-8 levels ranged widely from 4 to 7373 pg/mL. Highest IL-8 levels were observed on the day of intubation with subsequent tapering. Levels of IL-8 varied significantly across primary diagnoses with the highest levels occurring in patients with sepsis and the lowest levels in those with asthma. Plasma IL-8 was strongly correlated with oxygenation defect and severity of illness. IL-8 was consistently higher in PARDS patients compared to those without PARDS; levels were 4–12 fold higher in non-survivors compared to survivors. On multivariable analysis, IL-8 was independently associated with death, duration of mechanical ventilation, and PICU length of stay on all days measured, but was not associated with PARDS development. There was no association between the IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, and PARDS development or plasma IL-8 level. Conclusions When measured sequentially, plasma IL-8 was robustly associated with multiple, relevant clinical outcomes including mortality, but was not associated with PARDS development. The wide range of plasma IL-8 levels exhibited in this cohort suggests that further study into the heterogeneity of this patient population and its impact on individual responses to PARDS treatment is warranted.

Non-invasive ventilation can prevent respiratory failure after extubation in individuals at increased risk of this complication, and enhanced survival in patients with hypercapnia has been recorded. We aimed to assess prospectively the effectiveness of non-invasive ventilation after extubation in patients with hypercapnia and as rescue therapy when respiratory failure develops. We undertook a randomised controlled trial in three intensive-care units in Spain. We enrolled 106 mechanically ventilated patients with chronic respiratory disorders and hypercapnia after a successful spontaneous breathing trial. We randomly allocated participants by computer to receive after extubation either non-invasive ventilation for 24 h (n=54) or conventional oxygen treatment (n=52). The primary endpoint was avoidance of respiratory failure within 72 h after extubation. Analysis was by intention to treat. This trial is registered with clinicaltrials.gov, identifier NCT00539708. Respiratory failure after extubation was less frequent in patients assigned non-invasive ventilation than in those allocated conventional oxygen therapy (8 [15%] vs 25 [48%]; odds ratio 5·32 [95% CI 2·11–13·46]; p<0·0001). In patients with respiratory failure, non-invasive ventilation as rescue therapy avoided reintubation in 17 of 27 patients. Non-invasive ventilation was independently associated with a lower risk of respiratory failure after extubation (adjusted odds ratio 0·17 [95% CI 0·06–0·44]; p<0·0001). 90-day mortality was lower in patients assigned non-invasive ventilation than in those allocated conventional oxygen (p=0·0146). Early non-invasive ventilation after extubation diminished risk of respiratory failure and lowered 90-day mortality in patients with hypercapnia during a spontaneous breathing trial. Routine implementation of this strategy for management of mechanically ventilated patients with chronic respiratory disorders is advisable. IDIBAPS, CibeRes, Fondo de Investigaciones Sanitarias, European Respiratory Society.

COVID-19 disease is associated with a hyperinflammatory, pro-thrombotic state and a high mortality. Our primary objective was to assess the change in inflammatory and thrombotic markers associated with PEX, and secondary objectives were to assess the effects of PEX on progression of respiratory failure and incidence of acute thrombotic events. We conducted a prospective, phase II, non-blinded randomised control trial of plasma exchange compared to standard of care in critically ill adults with severe COVID-19 associated respiratory failure, requiring supplemental oxygen or ventilatory support and elevated thrombo-inflammatory markers (LDH, CRP, ferritin, and D-Dimer). Patients randomised to receive PEX were treated with a daily single volume plasma exchange for a minimum of five days. Twenty-two patients were randomised of who 11 received PEX. Demographic and clinical characteristics were similar between groups at presentation. PEX was associated with a significant reduction in pro-thrombotic markers FVIII, VWF and VWF Ag: ADAMTS 13 ratio ( p  < 0.001). There were no differences in the reduction of inflammatory markers, severity of respiratory failure ( p  = 0.7), thrombotic events ( p  = 0.67), or mortality ( p  > 0.99) at 28 days. PEX successfully reduced pro-thrombotic markers, although was not associated with reduction in inflammatory markers, respiratory failure, or thrombotic events. Trial registration : (NCT04623255); first posted on 10/11/2020.

Background: Long term non-invasive ventilation (NIV) reduces morbidity and mortality in patients with neuromuscular and chest wall disease with hypercapnic ventilatory failure, but preventive use has not produced benefit in normocapnic patients with Duchenne muscular dystrophy. Individuals with nocturnal hypercapnia but daytime normocapnia were randomised to a control group or nocturnal NIV to examine whether nocturnal hypoventilation is a valid indication for NIV. Methods: Forty eight patients with congenital neuromuscular or chest wall disease aged 7–51 years and vital capacity <50% predicted underwent overnight respiratory monitoring. Twenty six with daytime normocapnia and nocturnal hypercapnia were randomised to either nocturnal NIV or to a control group without ventilatory support. NIV was started in the control group if patients fulfilled preset safety criteria. Results: Peak nocturnal transcutaneous carbon dioxide tension (Tcco2) did not differ between the groups, but the mean (SD) percentage of the night during which Tcco2 was >6.5 kPa decreased in the NIV group (−57.7 (26.1)%) but not in controls (−11.75 (46.1)%; p = 0.049, 95% CI −91.5 to −0.35). Mean (SD) arterial oxygen saturation increased in the NIV group (+2.97 (2.57)%) but not in controls (−1.12 (2.02)%; p = 0.024, 95% CI 0.69 to 7.5). Nine of the 10 controls failed non-intervention by fulfilling criteria to initiate NIV after a mean (SD) of 8.3 (7.3) months. Conclusion: Patients with neuromuscular disease with nocturnal hypoventilation are likely to deteriorate with the development of daytime hypercapnia and/or progressive symptoms within 2 years and may benefit from the introduction of nocturnal NIV before daytime hypercapnia ensues.

Background Noninvasive ventilation (NIV) is used in critically ill patients with acute respiratory failure (ARF) to avoid endotracheal intubation. However, the impact of NIV use on ARF patient’s outcomes is still unclear. Our objectives were to evaluate the rate of NIV failure in hypoxemic patients with an arterial carbon dioxide partial pressure (PaCO 2 ) < 45 mmHg or ≥ 45 mmHg at ICU admission, the predictors of NIV failure, ICU and hospital length of stay and 28-day mortality. Methods Prospective single center cohort study. All consecutive patients admitted to a mixed ICU during a three-month period who received NIV, except for palliative care purposes, were included in this study. Demographic data, APACHE II score, cause of ARF, number of patients that received NIV, incidence of NIV failure, length of ICU, hospital stay and mortality rate were compared between NIV failure and success groups. Results Eighty-five from 462 patients (18.4 %) received NIV and 26/85 (30.6 %) required invasive mechanical ventilation. NIV failure patients were comparatively younger (67 ± 21 vs. 77 ± 14 years; p = 0.031), had lower arterial bicarbonate ( p = 0.005), lower PaCO 2 levels ( p = 0.032), higher arterial lactate levels ( p = 0.046) and APACHE II score ( p = 0.034) compared to NIV success patients. NIV failure occurred in 25.0 % of patients with PaCO 2 ≥ 45 mmHg and in 33.3 % of patients with PaCO 2 < 45 mmHg ( p = 0.435). NIV failure was associated with an increased risk of in-hospital death (OR 4.64, 95 % CI 1.52 to 14.18; p = 0.007) and length [median (IQR)] of ICU [12 days (8–31) vs. 2 days (1–4); p < 0.001] and hospital [30 (19–42) vs. 15 (9–33) days; p = 0.010] stay. Predictors of NIV failure included age (OR 0.96, 95 % CI 0.93 to 0.99; p = 0.007) and APACHE II score (OR 1.13, 95 % CI 1.02 to 1.25; p = 0.018). Conclusion NIV failure was associated with an increased risk of in-hospital death, ICU and hospital stay and was not affected by baseline PaCO 2 levels. Patients that failed were comparatively younger and had higher APACHE II score, suggesting the need for a careful selection of patients that might benefit from NIV. A well-designed study on the impact of a short monitored NIV trial on outcomes is needed.

Background: Noninvasive positive-pressure ventilation (NPPV) using intelligent volume-assured pressure support (iVAPS) combines volume- and pressure-preset NPPV and therefore uses a variation of inspiratory positive airway pressures. Objectives: The effect of iVAPS on sleep quality in stable hypercapnic patients with chronic obstructive pulmonary disease (COPD) has not been determined. Methods: In this randomized, open-label, two-treatment, two-period, crossover study, patients were randomized to receive high-intensity (HI)-NPPV and then iVAPS or iVAPS and then HI-NPPV. Patients were studied in hospital for 2 consecutive nights, employing full polysomnography (PSG), transcutaneous partial pressure of CO 2 (PtcCO 2 ) monitoring, blood gas analysis and a visual analog scale (VAS)-based sleep questionnaire. After discharge, patients used HI-NPPV and iVAPS at home, each for 6 weeks. They had to answer a VAS question concerning sleep every morning, and were telephoned weekly and asked additional questions. At the end of each treatment period, they were visited at home for the determination of blood gases and treatment adherence, and to change the NPPV mode. Results: Fourteen patients were enrolled. In-hospital PSG measurements showed no difference in sleep quality between iVAPS and HI-NPPV. At home, patients reported more restful sleep during iVAPS than HI-NPPV (p = 0.04). Blood gases during spontaneous breathing at home did not differ with iVAPS and HI-NPPV, and there was a greater decrease in PtcCO 2 during iVAPS than during HI-NPPV (p = 0.003). Conclusion: Although sleep quality in hospital was not different between iVAPS and HI-NPPV, COPD patients with chronic hypercapnic respiratory failure reported a trend towards more restful sleep at home with iVAPS. In addition, nocturnal hypercapnia was effectively treated with iVAPS.

Background Patients with Acute Hypercapnic Respiratory Failure (AHRF) who are unresponsive to appropriate medical treatment, are often treated with Noninvasive Positive Pressure Ventilation (NPPV). Clinical predictors of the outcome of this treatment are scarce. Therefore, we evaluated the role of the biomarkers IL-8 and GDF-15 in predicting 28-day mortality in patients with AHRF who receive treatment with NPPV. Methods The study population were 46 patients treated with NPPV for AHRF. Clinical and background data was registered and blood samples taken for analysis of inflammatory biomarkers. IL-8 and GDF-15 were selected for analysis, and related to risk of 28-day mortality (primary endpoint) using Cox proportional hazard models adjusted for gender, age and various clinical parameters. Results Of the 46 patients, there were 3 subgroup in regards to primary diagnosis: Acute Exacerbation of COPD (AECOPD, n  = 34), Acute Heart Failure (AHF, n  = 8) and Acute Exacerbation in Obesity Hypoventilation Syndrome (AEOHS, n  = 4). There was significant difference in the basic characteristic of the subgroups, but not in the clinical parameters that were used in treatment decisions. 13 patients died within 28 days of admission (28%). The Hazard Ratio for 28-days mortality per 1-SD increment of IL-8 was 3.88 (95% CI 1.86–8.06, p  < 0.001). When IL-8 values were divided into tertiles, the highest tertile had a significant association with 28 days mortality, HR 10.02 (95% CI 1.24–80.77, p for trend 0.03), compared with the lowest tertile. This correlation was maintained when the largest subgroup with AECOPD was analyzed. GDF-15 was correlated in the same way, but when put into the same model as IL-8, the significance disappeared. Conclusion IL-8 is a target to explore further as a predictor of 28 days mortality, in patients with AHRF treated with NPPV.

Background: Midazolam is commonly used for sedation during flexible bronchoscopy because of its relatively wide therapeutic window. Recently, sedation with propofol for bronchoscopy has gained popularity, although concern has been raised regarding its potential ability to induce severe respiratory depression. Objectives: The aim of this study was to evaluate the safety of sedation under midazolam + alfentanil compared to propofol. Methods: We conducted a prospective randomized trial using continuous transcutaneous carbon dioxide tension monitoring. The study group included 115 patients undergoing bronchoscopy, prospectively randomized to receive sedation with either midazolam + alfentanil (n = 59) or propofol (n = 56). Results: Intra-procedural carbon dioxide tension values were higher in the midazolam + alfentanil group than in the propofol group (maximum 53.72 vs. 49.49 mm Hg, mean 46.78 vs. 43.78 mm Hg), but the differences did not reach statistical significance (p = 0.149 and 0.193, respectively). Carbon dioxide tension values were significantly higher in the midazolam + alfentanil group than in the propofol group at 5 and 10 min following procedure (51.7 vs. 49.3 mm Hg, p = 0.026, and 50.8 vs. 42.7 mm Hg, p < 0.01, respectively), and significantly more patients in the midazolam + alfentanil group needed oxygen supplementation or airway support (24 vs. 8 patients, respectively). Conclusion: Midazolam + alfentanil and propofol are equally safe for sedation during bronchoscopy. Sedation with propofol, using small boluses at short intervals, does not cause excessive respiratory drive depression and represents an excellent alternative to traditional sedation agents.