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One-lung ventilation in thoracic surgery provokes profound systemic inflammatory responses and injury related to lung tidal volume changes. We hypothesized that the highly selective a2-adrenergic agonist dexmedetomidine attenuates these injurious responses. Sixty patients were randomly assigned to receive dexmedetomidine or saline during thoracoscopic surgery. There is a trend of less postoperative medical complication including that no patients in the dexmedetomidine group developed postoperative medical complications, whereas four patients in the saline group did (0% versus 13.3%, p=0.1124). Plasma inflammatory and injurious biomarkers between the baseline and after resumption of two-lung ventilation were particularly notable. The plasma high-mobility group box 1 level decreased significantly from 51.7 (58.1) to 33.9 (45.0) ng.ml−1 (p<0.05) in the dexmedetomidine group, which was not observed in the saline group. Plasma monocyte chemoattractant protein 1 [151.8 (115.1) to 235.2 (186.9) pg.ml−1, p<0.05] and neutrophil elastase [350.8 (154.5) to 421.9 (106.1) ng.ml−1, p<0.05] increased significantly only in the saline group. In addition, plasma interleukin-6 was higher in the saline group than in the dexmedetomidine group at postoperative day 1 [118.8 (68.8) versus 78.5 (58.8) pg.ml−1, p=0.0271]. We conclude that dexmedetomidine attenuates one-lung ventilation-associated inflammatory and injurious responses by inhibiting alveolar neutrophil recruitment in thoracoscopic surgery.

Purpose To improve the outcome of the acute respiratory distress syndrome (ARDS), one needs to identify potentially modifiable factors associated with mortality. Methods The large observational study to understand the global impact of severe acute respiratory failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across five continents. A pre-specified secondary aim was to examine the factors associated with outcome. Analyses were restricted to patients (93.1 %) fulfilling ARDS criteria on day 1–2 who received invasive mechanical ventilation. Results 2377 patients were included in the analysis. Potentially modifiable factors associated with increased hospital mortality in multivariable analyses include lower PEEP, higher peak inspiratory, plateau, and driving pressures, and increased respiratory rate. The impact of tidal volume on outcome was unclear. Having fewer ICU beds was also associated with higher hospital mortality. Non-modifiable factors associated with worsened outcome from ARDS included older age, active neoplasm, hematologic neoplasm, and chronic liver failure. Severity of illness indices including lower pH, lower PaO 2 /FiO 2 ratio, and higher non-pulmonary SOFA score were associated with poorer outcome. Of the 578 (24.3 %) patients with a limitation of life-sustaining therapies or measures decision, 498 (86.0 %) died in hospital. Factors associated with increased likelihood of limitation of life-sustaining therapies or measures decision included older age, immunosuppression, neoplasia, lower pH and increased non-pulmonary SOFA scores. Conclusions Higher PEEP, lower peak, plateau, and driving pressures, and lower respiratory rate are associated with improved survival from ARDS. Trial Registration: ClinicalTrials.gov NCT02010073.

Background Pulse pressure variation (PPV) has been widely used in hemodynamic assessment. Nevertheless, PPV is limited in low tidal volume ventilation. We conducted this systematic review and meta-analysis to evaluate whether the tidal volume challenge (TVC) could improve the feasibility of PPV in patients ventilated at low tidal volumes. Methods PubMed, Embase and Cochrane Library inception to October 2022 were screened for diagnostic researches relevant to the predictability of PPV change after TVC in low tidal volume ventilatory patients. Summary receiving operating characteristic curve (SROC), pooled sensitivity and specificity were calculated. Subgroup analyses were conducted for possible influential factors of TVC. Results Ten studies with a total of 429 patients and 457 measurements were included for analysis. The predictive performance of PPV was significantly lower than PPV change after TVC in low tidal volume, with mean area under the receiving operating characteristic curve (AUROC) of 0.69 ± 0.13 versus 0.89 ± 0.10. The SROC of PPV change yielded an area under the curve of 0.96 (95% CI 0.94, 0.97), with overall pooled sensitivity and specificity of 0.92 (95% CI 0.83, 0.96) and 0.88 (95% CI 0.76, 0.94). Mean and median cutoff value of the absolute change of PPV (△PPV) were 2.4% and 2%, and that of the percentage change of PPV (△PPV%) were 25% and 22.5%. SROC of PPV change in ICU group, supine or semi-recumbent position group, lung compliance less than 30 cm H 2 O group, moderate positive end-expiratory pressure (PEEP) group and measurements devices without transpulmonary thermodilution group yielded 0.95 (95%0.93, 0.97), 0.95 (95% CI 0.92, 0.96), 0.96 (95% CI 0.94, 0.97), 0.95 (95% CI 0.93, 0.97) and 0.94 (95% CI 0.92, 0.96) separately. The lowest AUROCs of PPV change were 0.59 (95% CI 0.31, 0.88) in prone position and 0.73 (95% CI 0.60, 0.84) in patients with spontaneous breathing activity. Conclusions TVC is capable to help PPV overcome limitations in low tidal volume ventilation, wherever in ICU or surgery. The accuracy of TVC is not influenced by reduced lung compliance, moderate PEEP and measurement tools, but TVC should be cautious applied in prone position and patients with spontaneous breathing activity. Trial registration PROSPERO (CRD42022368496). Registered on 30 October 2022.

Introduction Lung protective ventilation (LPV) comprising low tidal volume (VT) and high positive end-expiratory pressure (PEEP) may compromise cerebral perfusion in acute brain injury (ABI). In patients with ABI, we investigated whether LPV is associated with increased intracranial pressure (ICP) and/or deranged cerebral autoregulation (CA), brain compensatory reserve and oxygenation. Methods In a prospective, crossover study, 30 intubated ABI patients with normal ICP and no lung injury were randomly assigned to receive low VT [6 ml/kg/predicted (pbw)]/at either low (5 cmH 2 O) or high PEEP (12 cmH 2 O). Between each intervention, baseline ventilation (VT 9 ml/kg/pbw and PEEP 5 cmH 2 O) were resumed. The safety limit for interruption of the intervention was ICP above 22 mmHg for more than 5 min. Airway and transpulmonary pressures were continuously monitored to assess respiratory mechanics. We recorded ICP by using external ventricular drainage or a parenchymal probe. CA and brain compensatory reserve were derived from ICP waveform analysis. Results We included 27 patients (intracerebral haemorrhage, traumatic brain injury, subarachnoid haemorrhage), of whom 6 reached the safety limit, which required interruption of at least one intervention. For those without intervention interruption, the ICP change from baseline to “low VT/low PEEP” and “low VT/high PEEP” were 2.2 mmHg and 2.3 mmHg, respectively, and considered clinically non-relevant. None of the interventions affected CA or oxygenation significantly. Interrupted events were associated with high baseline ICP ( p  < 0.001), low brain compensatory reserve ( p  < 0.01) and mechanical power ( p  < 0.05). The transpulmonary driving pressure was 5 ± 2 cmH 2 O in both interventions. Partial arterial pressure of carbon dioxide was kept in the range 34–36 mmHg by adjusting the respiratory rate, hence, changes in carbon dioxide were not associated with the increase in ICP. Conclusions The present study found that most patients did not experience any adverse effects of LPV, neither on ICP nor CA. However, in almost a quarter of patients, the ICP rose above the safety limit for interrupting the interventions. Baseline ICP, brain compensatory reserve, and mechanical power can predict a potentially deleterious effect of LPV and can be used to personalize ventilator settings. Trial registration NCT03278769 . Registered September 12, 2017. Graphical Abstract

Purpose: To evaluate whether a perioperative open-lung ventilation strategy prevents postoperative pulmonary complications after elective on-pump cardiac surgery.Methods: In a pragmatic, randomized, multicenter, controlled trial, we assigned patients planned for on-pump cardiac surgery to either a conventional ventilation strategy with no ventilation during cardiopulmonary bypass (CPB) and lower perioperative positive end-expiratory pressure (PEEP) levels (2 cm H2O) or an open-lung ventilation strategy that included maintaining ventilation during CPB along with perioperative recruitment maneuvers and higher PEEP levels (8 cm H2O). All study patients were ventilated with low-tidal volumes before and after CPB (6 to 8 ml/kg of predicted body weight). The primary end point was a composite of pulmonary complications occurring within the first 7 postoperative days.Results: Among 493 randomized patients, 488 completed the study (mean age, 65.7 years; 360 (73.7%) men; 230 (47.1%) underwent isolated valve surgery). Postoperative pulmonary complications occurred in 133 of 243 patients (54.7%) assigned to open-lung ventilation and in 145 of 245 patients (59.2%) assigned to conventional ventilation (p = 0.32). Open-lung ventilation did not significantly reduce the use of high-flow nasal oxygenotherapy (8.6% vs 9.4%; p = 0.77), non-invasive ventilation (13.2% vs 15.5%; p = 0.46) or new invasive mechanical ventilation (0.8% vs 2.4%, p = 0.28). Mean alive ICU-free days at postoperative day 7 was 4.4 ± 1.3 days in the open-lung group vs 4.3 ± 1.3 days in the conventional group (mean difference, 0.1 ± 0.1 day, p = 0.51). Extra-pulmonary complications and adverse events did not significantly differ between groups.Conclusions: A perioperative open-lung ventilation including ventilation during CPB does not reduce the incidence of postoperative pulmonary complications as compared with usual care. This finding does not support the use of such a strategy in patients undergoing on-pump cardiac surgery.

Background Although low tidal volume is strongly recommended for acute respiratory distress syndrome (ARDS), whether or not the benefit varies according to the severity of ARDS remains unclear. This study aimed to investigate whether or not there is an interaction between low tidal volume and severity of ARDS. Methods This was a secondary analysis from a randomized controlled trial. The patients were subgrouped according to whether the PaO 2 /FiO 2 (P/F) was > 150 or ≤ 150 mmHg on day 0. The interaction between a tidal volume of 6 mL/kg and the P/F was investigated in hierarchical chi-square analysis and logistic regression models. Results Eight hundred and thirty-six patients with ARDS were enrolled (345 in the high P/F subgroup [> 150 mmHg] and 491 in the low P/F subgroup [≤ 150 mmHg]). Compared to the traditional tidal volume group, the mortality of patients with low tidal volume was significantly lower in the high P/F subgroup (41/183 (22.4%) vs. 64/162 (39.5%), p  = 0.001) but not in the low P/F subgroup (95/256 (37.1%) vs. 96/235 (40.8%), p  = 0.414). In the hierarchical chi-square analysis, the test of homogeneity was significant (risk ratio of mortality 0.56 [0.40–0.79] vs. 0.91 [0.73–1.13], p  = 0.018). In the multivariable logistic model, the odds ratio of mortality for the interacted item was significant (2.02, 95% confidence interval [CI] 1.06–3.86, p  = 0.033). The odds ratio of mortality for low tidal volume was significant in the high P/F subgroup (0.42, 95% CI 0.24–0.72, p  = 0.002) but not in the low P/F subgroup (0.89, 95% CI 0.60–1.31, p  = 0.554). Conclusions The benefits of low tidal volume ventilation remain uncertain in patients with severe ARDS. Further studies are needed to validate this significant interaction.

IntroductionLower tidal volume ventilation, facilitated by veno-venous extracorporeal carbon dioxide removal (vv-ECCO2R), does not improve 90-day mortality in patients with acute hypoxaemic respiratory failure (AHRF). The aim of this analysis was to evaluate the effect of this therapeutic strategy on long-term outcomes.MethodsThis was a prespecified analysis of the REST trial, a UK-wide multicentre randomised clinical trial that compared lower tidal volume ventilation, facilitated by vv-ECCO2R (intervention), with standard care in the treatment of patients with moderate-to-severe AHRF. Mortality to 2 years was assessed, while respiratory function, post-traumatic stress disorder, cognitive function and health-related quality of life were evaluated in survivors at 1 year using standardised questionnaires.ResultsOf 412 patients enrolled into the REST trial, 391 (95%) had 2-year mortality outcome data available. There was no difference in the time to death between intervention and standard care (HR 1.08 (0.81, 1.44); log-rank test p=0.61). 161 patients alive at 1 year provided at least one questionnaire response. There was no difference in respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life between patients allocated to intervention or standard care.ConclusionLower-tidal volume ventilation facilitated by vv-ECCO2R does not affect 1-year mortality in patients with moderate-to-severe AHRF. Of the patients who provided questionnaire responses, there was no treatment effect on long-term respiratory function, post-traumatic stress disorder, cognitive dysfunction or health-related quality of life.Trial registration numberClinicalTrials.gov identifier: NCT02654327.

Background Inhaled furosemide offers a potentially novel treatment for dyspnoea, which may reflect modulation of pulmonary stretch receptor feedback to the brain. Specificity of relief is unclear because different neural pathways may account for different components of clinical dyspnoea. Our objective was to evaluate if inhaled furosemide relieves the air hunger component (uncomfortable urge to breathe) but not the sense of breathing work/effort of dyspnoea. Methods A randomised, double blind, placebo-controlled crossover trial in 16 healthy volunteers studied in a university research laboratory. Each participant received 3 mist inhalations (either 40 mg furosemide or 4 ml saline) separated by 30–60 min on 2 test days. Each participant was randomised to mist order ‘furosemide-saline-furosemide’ (n- = 8) or ‘saline-furosemide-saline’ ( n  = 8) on both days. One day involved hypercapnic air hunger tests (mean ± SD PCO 2  = 50 ± 3.7 mmHg; constrained ventilation = 9 ± 1.5 L/min), the other involved work/effort tests with targeted ventilation (17 ± 3.1 L/min) and external resistive load (20cmH 2 O/L/s). Primary outcome was ratings of air hunger or work/effort every 15 s on a visual analogue scale. During saline inhalations, 1.5 mg furosemide was infused intravenously to match the expected systemic absorption from the lungs when furosemide is inhaled. Corresponding infusions of saline during furosemide inhalations maintained procedural blinding. Average visual analogue scale ratings (%full scale) during the last minute of air hunger or work/effort stimuli were analysed using Linear Mixed Methods. Results Data from all 16 participants were analysed. Inhaled furosemide relative to inhaled saline significantly improved visual analogues scale ratings of air hunger (Least Squares Mean ± SE − 9.7 ± 2%; p  = 0.0015) but not work/effort (+ 1.6 ± 2%; p  = 0.903). There were no significant adverse events. Conclusions Inhaled furosemide was effective at relieving laboratory induced air hunger but not work/effort in healthy adults; this is consistent with the notion that modulation of pulmonary stretch receptor feedback by inhaled furosemide leads to dyspnoea relief that is specific to air hunger, the most unpleasant quality of dyspnoea. Funding Oxford Brookes University Central Research Fund. Trial registration ClinicalTrials.gov Identifier: NCT02881866 . Retrospectively registered on 29th August 2018.

PurposeThe aim of this study was to compare the effect of a pressure-controlled strategy allowing non-synchronised unassisted spontaneous ventilation (PC-SV) to a conventional volume assist-control strategy (ACV) on the outcome of patients with acute respiratory distress syndrome (ARDS).MethodsOpen-label randomised clinical trial in 22 intensive care units (ICU) in France. Seven hundred adults with moderate or severe ARDS (PaO2/FiO2 < 200 mmHg) were enrolled from February 2013 to October 2018. Patients were randomly assigned to PC-SV (n = 348) or ACV (n = 352) with similar objectives of tidal volume (6 mL/kg predicted body weight) and positive end-expiratory pressure (PEEP). Paralysis was stopped after 24 h and sedation adapted to favour patients’ spontaneous ventilation. The primary endpoint was in-hospital death from any cause at day 60.ResultsHospital mortality [34.6% vs 33.5%, p = 0.77, risk ratio (RR) = 1.03 (95% confidence interval [CI] 0.84–1.27)], 28-day mortality, as well as the number of ventilator-free days and organ failure-free days at day 28 did not differ between PC-SV and ACV groups. Patients in the PC-SV group received significantly less sedation and neuro-muscular blocking agents than in the ACV group. A lower proportion of patients required adjunctive therapy of hypoxemia (including prone positioning) in the PC-SV group than in the ACV group [33.1% vs 41.3%, p = 0.03, RR = 0.80 (95% CI 0.66–0.98)]. The incidences of pneumothorax and refractory hypoxemia did not differ between the groups.ConclusionsA strategy based on PC-SV mode that favours spontaneous ventilation reduced the need for sedation and adjunctive therapies of hypoxemia but did not significantly reduce mortality compared to ACV with similar tidal volume and PEEP levels.

Abstract Rationale Low–tidal volume ventilation (LTVV; 6 ml/kg) benefits patients with acute respiratory distress syndrome and may aid those with other causes of respiratory failure. Current early ventilation practices are poorly defined. Objectives We observed patients with acute respiratory failure to assess the feasibility of a pragmatic trial of LTVV and to guide experimental design. Methods We prospectively enrolled consecutive patients with acute respiratory failure admitted to intensive care units expected to participate in the proposed trial. We collected clinical data as well as information on initial and daily ventilator settings and inpatient mortality. We estimated the benefit of LTVV using predictive linear and nonlinear models. We simulated models to estimate power and feasibility of a cluster-randomized trial of LTVV versus usual care in acute respiratory failure. Results We included 2,484 newly mechanically ventilated patients (31% with acute respiratory distress syndrome) from 49 hospitals. Hospital mortality was 28%. Mean initial tidal volume was 7.1 ml/kg predicted body weight (95% confidence interval, 7.1–7.2), with 78% of patients receiving tidal volumes less than or equal to 8 ml/kg. Our models estimated a mortality benefit of 0–2% from LTVV compared with usual care. Simulation of a stepped-wedged cluster-randomized trial suggested that enrollment of 106,361 patients would be necessary to achieve greater than 90% power. Conclusions Use of initial tidal volumes less than 8 ml/kg predicted body weight was common at hospitals participating in the National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury (PETAL) Network. After considering the size and budgetary requirement for a cluster-randomized trial of LTVV versus usual care in acute respiratory failure, the PETAL Network deemed the proposed trial infeasible. A rapid observational study and simulations to model anticipated power may help better design trials.