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PurposeWe assessed the effects of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO2) and normoxia or moderate hyperoxia after out-of-hospital cardiac arrest (OHCA) on markers of cerebral and cardiac injury.MethodsUsing a 23 factorial design, we randomly assigned 123 patients resuscitated from OHCA to low-normal (4.5–4.7 kPa) or high-normal (5.8–6.0 kPa) PaCO2 and to normoxia (arterial oxygen tension [PaO2] 10–15 kPa) or moderate hyperoxia (PaO2 20–25 kPa) and to low-normal or high-normal mean arterial pressure during the first 36 h in the intensive care unit. Here we report the results of the low-normal vs. high-normal PaCO2 and normoxia vs. moderate hyperoxia comparisons. The primary endpoint was the serum concentration of neuron-specific enolase (NSE) 48 h after cardiac arrest. Secondary endpoints included S100B protein and cardiac troponin concentrations, continuous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) results and neurologic outcome at 6 months.ResultsIn total 120 patients were included in the analyses. There was a clear separation in PaCO2 (p < 0.001) and PaO2 (p < 0.001) between the groups. The median (interquartile range) NSE concentration at 48 h was 18.8 µg/l (13.9–28.3 µg/l) in the low-normal PaCO2 group and 22.5 µg/l (14.2–34.9 µg/l) in the high-normal PaCO2 group, p = 0.400; and 22.3 µg/l (14.8–27.8 µg/l) in the normoxia group and 20.6 µg/l (14.2–34.9 µg/l) in the moderate hyperoxia group, p = 0.594). High-normal PaCO2 and moderate hyperoxia increased NIRS values. There were no differences in other secondary outcomes.ConclusionsBoth high-normal PaCO2 and moderate hyperoxia increased NIRS values, but the NSE concentration was unaffected.RegistrationClinicalTrials.gov, NCT02698917. Registered on January 26, 2016.

Background Acute respiratory distress syndrome is characterized by damage to the lung caused by various insults, including ventilation itself, and tidal hyperinflation can lead to ventilator induced lung injury (VILI). We investigated the effects of a low tidal volume ( V T ) strategy ( V T  ≈ 3 ml/kg/predicted body weight [PBW]) using pumpless extracorporeal lung assist in established ARDS. Methods Seventy-nine patients were enrolled after a ‘stabilization period’ (24 h with optimized therapy and high PEEP). They were randomly assigned to receive a low V T ventilation (≈3 ml/kg) combined with extracorporeal CO 2 elimination, or to a ARDSNet strategy (≈6 ml/kg) without the extracorporeal device. The primary outcome was the 28-days and 60-days ventilator-free days (VFD). Secondary outcome parameters were respiratory mechanics, gas exchange, analgesic/sedation use, complications and hospital mortality. Results Ventilation with very low V T ’s was easy to implement with extracorporeal CO 2 -removal. VFD’s within 60 days were not different between the study group (33.2 ± 20) and the control group (29.2 ± 21, p  = 0.469), but in more hypoxemic patients (PaO 2 /FIO 2 ≤150) a post hoc analysis demonstrated significant improved VFD-60 in study patients (40.9 ± 12.8) compared to control (28.2 ± 16.4, p  = 0.033). The mortality rate was low (16.5 %) and did not differ between groups. Conclusions The use of very low V T combined with extracorporeal CO 2 removal has the potential to further reduce VILI compared with a ‘normal’ lung protective management. Whether this strategy will improve survival in ARDS patients remains to be determined (Clinical trials NCT 00538928).

Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.

In a trial involving patients with coma after out-of-hospital cardiac arrest, a strategy targeting mild hypercapnia for 24 hours did not improve neurologic outcomes at 6 months as compared with targeted normocapnia.

Background:Sleep hypoventilation has been proposed as a cause of progressive hypercapnic respiratory failure and death in patients with severe chronic obstructive pulmonary disease (COPD). A study was undertaken to determine the effects of nocturnal non-invasive bi-level pressure support ventilation (NIV) on survival, lung function and quality of life in patients with severe hypercapnic COPD.Method:A multicentre, open-label, randomised controlled trial of NIV plus long-term oxygen therapy (LTOT) versus LTOT alone was performed in four Australian University Hospital sleep/respiratory medicine departments in patients with severe stable smoking-related COPD (forced expiratory volume in 1 s (FEV1.0) <1.5 litres or <50% predicted and ratio of FEV1.0 to forced vital capacity (FVC) <60% with awake arterial carbon dioxide tension (Paco2) >46 mm Hg and on LTOT for at least 3 months) and age <80 years. Patients with sleep apnoea (apnoea-hypopnoea index >20/h) or morbid obesity (body mass index >40) were excluded. Outcome measures were survival, spirometry, arterial blood gases, polysomnography, general and disease-specific quality of life and mood.Results:144 patients were randomised (72 to NIV + LTOT and 72 to LTOT alone). NIV improved sleep quality and sleep-related hypercapnia acutely, and patients complied well with therapy (mean (SD) nightly use 4.5 (3.2) h). Compared with LTOT alone, NIV (mean follow-up 2.21 years, range 0.01–5.59) showed an improvement in survival with the adjusted but not the unadjusted Cox model (adjusted hazard ratio (HR) 0.63, 95% CI 0.40 to 0.99, p = 0.045; unadjusted HR 0.82, 95% CI 0.53 to 1.25, p = NS). FEV1.0 and Paco2 measured at 6 and 12 months were not different between groups. Patients assigned to NIV + LTOT had reduced general and mental health and vigour.Conclusions:Nocturnal NIV in stable oxygen-dependent patients with hypercapnic COPD may improve survival, but this appears to be at the cost of worsening quality of life.Trial registration number:ACTRN12605000205639

We studied the effects of high flow oxygen therapy (HFOT) versus non-invasive ventilation (NIV) on inspiratory effort, as assessed by measuring transdiaphragmatic pressure, breathing pattern and gas exchange. Fourteen patients with hypercapnic COPD underwent five 30-min trials: HFOT at two flow rates, both with open and closed mouth, and NIV, applied in random order. After each trial standard oxygen therapy was reinstituted for 10 min. Compared with baseline, HFOT and NIV significantly improved breathing pattern, although to different extents, and reduced inspiratory effort; however, arterial carbon dioxide oxygen tension decreased but not significantly. These results indicate a possible role for HFOT in the long-term management of patients with stable hypercapnic COPD.Trial registration numberNCT02363920.

RationaleThe conventional approach of low-intensity non-invasive positive pressure ventilation (NPPV) produces only minimal physiological and clinical benefits in patients with stable hypercapnic chronic obstructive pulmonary disease (COPD).ObjectivesTo determine whether the novel approach of high-intensity NPPV is superior to low-intensity NPPV in controlling nocturnal hypoventilation.MethodsA randomised controlled crossover trial comparing 6 weeks of high-intensity NPPV (using controlled ventilation with mean inspiratory pressures of 28.6±1.9 mbar) with low-intensity NPPV (using assisted ventilation with mean inspiratory pressures of 14.6±0.8 mbar) was performed in 17 patients with severe stable hypercapnic COPD.ResultsTwo patients refused low-intensity NPPV and two patients dropped out while on low-intensity NPPV. Thirteen patients (mean forced expiratory volume in 1 s (FEV1) 0.76±0.29 l) completed the trial. High-intensity NPPV produced higher pneumotachographically-measured expiratory volumes, with a mean treatment effect of 96 ml (95% CI 23 to 169) (p=0.015). This resulted in a mean treatment effect on nocturnal arterial carbon dioxide tension (Paco2) of −9.2 mm Hg (95% CI −13.7 to −4.6) (p=0.001) in favour of high-intensity NPPV. Daily use of NPPV was increased in high-intensity NPPV compared with low-intensity NPPV, with a mean difference of 3.6 h/day (95% CI 0.6 to 6.7) (p=0.024). In addition, compared with baseline, only high-intensity NPPV resulted in significant improvements in exercise-related dyspnoea, daytime Paco2, FEV1, vital capacity and the Severe Respiratory Insufficiency Questionnaire Summary Score.ConclusionsHigh-intensity NPPV is better tolerated by patients with severe chronic hypercapnic COPD and has been shown to be superior to the conventional and widely-used form of low-intensity NPPV in controlling nocturnal hypoventilation. High-intensity NPPV therefore offers a new promising therapeutic option for these patients.

Background Although cumulative studies have demonstrated a beneficial effect of high-flow nasal cannula oxygen (HFNC) in acute hypercapnic respiratory failure, randomized trials to compare HFNC with non-invasive ventilation (NIV) as initial treatment in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) patients with acute-moderate hypercapnic respiratory failure are limited. The aim of this randomized, open label, non-inferiority trial was to compare treatment failure rates between HFNC and NIV in such patients. Methods Patients diagnosed with AECOPD with a baseline arterial blood gas pH between 7.25 and 7.35 and PaCO 2  ≥ 50 mmHg admitted to two intensive care units (ICUs) at a large tertiary academic teaching hospital between March 2018 and December 2022 were randomly assigned to HFNC or NIV. The primary endpoint was the rate of treatment failure, defined as endotracheal intubation or a switch to the other study treatment modality. Secondary endpoints were rates of intubation or treatment change, blood gas values, vital signs at one, 12, and 48 h, 28-day mortality, as well as ICU and hospital lengths of stay. Results 225 total patients (113 in the HFNC group and 112 in the NIV group) were included in the intention-to-treat analysis. The failure rate of the HFNC group was 25.7%, while the NIV group was 14.3%. The failure rate risk difference between the two groups was 11.38% (95% CI 0.25–21.20, P  = 0.033), which was higher than the non-inferiority cut-off of 9%. In the per-protocol analysis, treatment failure occurred in 28 of 110 patients (25.5%) in the HFNC group and 15 of 109 patients (13.8%) in the NIV group (risk difference, 11.69%; 95% CI 0.48–22.60). The intubation rate in the HFNC group was higher than in the NIV group (14.2% vs 5.4%, P  = 0.026). The treatment switch rate, ICU and hospital length of stay or 28-day mortality in the HFNC group were not statistically different from the NIV group (all P  > 0.05). Conclusion HFNC was not shown to be non-inferior to NIV and resulted in a higher incidence of treatment failure than NIV when used as the initial respiratory support for AECOPD patients with acute-moderate hypercapnic respiratory failure. Trial registration : chictr.org (ChiCTR1800014553). Registered 21 January 2018, http://www.chictr.org.cn

Despite the encouraging results of noninvasive ventilation (NIV) in chronic hypercapnic COPD patients, it is also evident that some patients do not tolerate NIV or do not benefit from it. We conducted a study in which COPD patients with stable, chronic hypercapnia were treated with NIV and nasal high-flow (NHF) to compare effectiveness. In a multi-centered, randomized, controlled, cross-over design, patients received 6 weeks of NHF ventilation followed by 6 weeks of NIV ventilation or vice-versa (TIBICO) between 2011 and 2016. COPD patients with stable daytime hypercapnia (pCO ≥50 mmHg) were recruited from 13 German centers. The primary endpoint was pCO changes from baseline blood gas, lung function, quality of life (QoL), the 6 min walking test, and duration of device use were secondary endpoints. A total of 102 patients (mean±SD) age 65.3±9.3 years, 61% females, body mass index 23.1±4.8 kg/m , 90% GOLD D, pCO 56.5±5.4 mmHg were randomized. PCO levels decreased by 4.7% (n=94; full analysis set; 95% CI 1.8-7.5, =0.002) using NHF and 7.1% (95% CI 4.1-10.1, <0.001) from baseline using NIV (indistinguishable to intention-to-treat analysis). The difference of pCO changes between the two devices was -1.4 mmHg (95% CI -3.1-0.4, =0.12). Both devices had positive impact on blood gases and respiratory scores (St. George's Respiratory Questionnaire, Severe Respiratory Insufficiency Questionnaire). NHF may constitute an alternative to NIV in COPD patients with stable chronic hypercapnia, eg, those not tolerating or rejecting NIV with respect to pCO reduction and improvement in QoL.

Introduction The effectiveness of non-invasive positive pressure ventilation (NIV) in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure (ARF) remains unclear. We investigated if nocturnal NIV in these patients prolongs the time to readmission for respiratory causes or death (primary endpoint) in the following 12 months. Methods 201 COPD patients admitted to hospital with ARF and prolonged hypercapnia >48 h after termination of ventilatory support were randomised to NIV or standard treatment. Secondary outcomes were daytime arterial blood gasses, transcutaneous PCO2 during the night, lung function, health-related quality-of-life (HRQL), mood state, daily activities and dyspnoea. Results 1 year after discharge, 65% versus 64% of patients (NIV vs standard treatment) were readmitted to hospital for respiratory causes or had died; time to event was not different (p=0.85). Daytime PaCO2 was significantly improved in NIV versus standard treatment (PaCO2 0.5 kPa (95% CI 0.04 to 0.90, p=0.03)) as was transcutaneous PCO2 during the night. HRQL showed a trend (p=0.054, Severe Respiratory Insufficiency questionnaire) in favour of NIV. Number of exacerbations, lung function, mood state, daily activity levels or dyspnoea was not significantly different. Discussions We could not demonstrate an improvement in time to readmission or death by adding NIV for 1 year in patients with prolonged hypercapnia after an episode of NIV for ARF. There is no reason to believe the NIV was not effective since daytime PaCO2 and night-time PCO2 improved. The trend for improvement in HRQL favouring NIV we believe nevertheless should be explored further. Trial registration number NTR1100.