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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.

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 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

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

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 Nasal Highflow (NHF) delivers a humidified and heated airflow via nasal prongs. Current data provide evidence for efficacy of NHF in patients with hypoxemic respiratory failure. Preliminary data suggest that NHF may decrease hypercapnia in hypercapnic respiratory failure. The aim of this study was to evaluate the mechanism of NHF mediated PCO 2 reduction in patients with chronic obstructive pulmonary disease (COPD). Methods In 36 hypercapnic COPD patients (PCO 2  > 45 mmHg), hypercapnia was evaluated by capillary gas sampling 1 h after NHF breathing under four conditions A to D with different flow rates and different degrees of leakage (A = 20 L/min, low leakage, two prongs, both inside; B = 40 L/min, low leakage, two prongs, both inside; C = 40 L/min, high leakage, two prongs, one outside and open; D = 40 L/min, high leakage, two prongs, one outside and closed). Under identical conditions, mean airway pressure was measured in the hypopharynx of 10 COPD patients. Results Hypercapnia significantly decreased in all patients. In patients with capillary PCO 2  > 55 mmHg ( n  = 26), PCO 2 additionally decreased significantly by increased leakage and/or flow rate in comparison to lower leakage/ flow rate conditions (A = 94.2 ± 8.2%; B = 93.5 ± 4.4%; C = 90.5 ± 7.2%; D = 86.8 ± 3.8%). The highest mean airway pressure was observed in patients breathing under condition B (2.3 ± 1.6 mbar; p  < 0.05). Conclusions This study demonstrates effective PCO 2 reduction with NHF therapy in stable hypercapnic COPD patients. This effect does not correlate with an increase in mean airway pressure but with increased leakage and airflow, indicating airway wash out and reduction of functional dead space as important mechanisms of NHF therapy. These results may be useful when considering NHF treatment in hypercapnic COPD patients. Trial registration Clinical Trials: NCT02504814; First posted July 22, 2015.

Purpose To evaluate the effects of acute hypercapnia induced by positive end-expiratory pressure (PEEP) variations at constant plateau pressure ( P plat ) in patients with severe acute respiratory distress syndrome (ARDS) on right ventricular (RV) function. Methods Prospective observational study in two academic intensive care units enrolling 11 adults with severe ARDS (PaO 2 /FiO 2 <150 mmHg at PEEP >5 cmH 2 O). We compared three ventilatory strategies, each used for 1 h, with P plat at 22 (20–25) cmH 2 O: low PEEP (5.4 cmH 2 O) or high PEEP (11.0 cmH 2 O) with compensation of the tidal volume reduction by either a high respiratory rate (high PEEP/high rate) or instrumental dead space decrease (high PEEP/low rate). We assessed RV function (transesophageal echocardiography), alveolar dead space (expired CO 2 ), and alveolar recruitment (pressure–volume curves). Results Compared to low PEEP, PaO 2 /FiO 2 ratio and alveolar recruitment were increased with high PEEP. Alveolar dead space remained unchanged. Both high-PEEP strategies induced higher PaCO 2 levels [71 (60–94) and 75 (53–84), vs. 52 (43–68) mmHg] and lower pH values [7.17 (7.12–7.23) and 7.20 (7.16–7.25) vs. 7.30 (7.24–7.35)], as well as RV dilatation, LV deformation and a significant decrease in cardiac index. The decrease in stroke index tended to be negatively correlated to the increase in alveolar recruitment with high PEEP. Conclusions Acidosis and hypercapnia induced by tidal volume reduction and increase in PEEP at constant P plat were associated with impaired RV function and hemodynamics despite positive effects on oxygenation and alveolar recruitment ( ClinicalTrials.gov #NCT00236262).

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.

There is no universally acceptable protocol for the withdrawal of non-invasive ventilation (NIV) in chronic obstructive pulmory disease (COPD) patients presenting with acute hypercapnic respiratory failure (AHcRF). This study was carried out to evaluate immediate against stepwise reduction in NIV. Sixty COPD patients with AHcRF who were maged with NIV were randomized into two groups: immediate NIV withdrawal (group A) and stepwise reduction of NIV duration (group B). The rate of successful NIV withdrawal, time to recurrence of hypercapnic respiratory failure, total duration of NIV use, and hospital length of stay (LOS) were compared among the two groups. NIV was successfully withdrawn in 51/60 (85 %) patients. NIV was successfully withdrawn in 24/30 (80%) patients in group A and 27/30 (90%) patients in group B (p=0.472). The total duration of NIV use was significantly lower in group A (38.97±17 hours) as compared to group B (64.3±7.74 hours) (p<0.0001). LOS was significantly lower in group A (5.8±1.6 days) as compared to group B (7.7±0.61 days) (p<0.0001). To conclude, immediate withdrawal of the NIV after recovery from respiratory failure among patients with exacerbation of COPD is feasible and does not increase the risk of weaning failure.

Background In acute exacerbation periods of chronic obstructive pulmonary disease (COPD), patients may experience hypoxemia or hypercapnia. Noninvasive ventilation (NIV) and respiratory stimulant drugs are used to treat this condition. Medroxyprogesterone acetate (MPA) can cross the blood-brain barrier and cause breathing stimulation and hyperventilation. This study was conducted to investigate the effectiveness of MPA in hypercapnic exacerbated COPD patients and the possibility of faster weaning of patients from NIV. Materials and methods This double-blind clinical trial was conducted on consecutive exacerbated COD patients referred to Shahid Rahnemoun Hospital, Yazd, Iran, from February 2022 to August 2022. Through a block randomized sampling method with a 1:1 allocation ratio, 58 eligible patients with hypercapnic exacerbated COPD on NIV were divided into two study groups: the intervention (treated with MPA 10 mg every 8 h) and the control (treated with placebo). The clinical and arterial blood gas (ABG) parameters were investigated in both groups. Results Out of 50 patients, 27 and 23 intervention and control arms cases were analyzed. Although there was a significant difference in the amount of ABG parameters during the study in each group, there was no statistically significant difference between the two groups. Also, There was no significant difference in the total weaning rate of the patients in the two groups. Despite the higher number of early weaning in the MPA group, no significant difference was reported between the two groups in this regard. In addition, there was no difference between the two groups in the rate of ICU hospitalization, the length of stay of hospitalization and ICU, and the mortality rate. Conclusion The administration of MPA has not improved clinical and laboratory results, and MPA is not superior to placebo in the weaning process of patients undergoing NIV. Trial registration IRCT20190810044500N21 (01/02/2022), (https//irct.behdasht.gov.ir/user/trial/59402/view)