Daily Respiratory Research Analysis

RATIONALE: Several non-invasive respiratory support modes are available to reduce extubation failure in preterm infants. However, their relative efficacy is unclear. OBJECTIVES: To assess the benefits and harms of non-invasive respiratory support modes for postextubation support in preterm infants. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science to January 2024. ELIGIBILITY CRITERIA: Randomised, quasi-randomised, and cluster-randomised controlled trials comparing non-invasive respiratory support modes for preterm infants postextubation. OUTCOMES: Critical outcomes included treatment failure, endotracheal ventilation, and moderate-severe chronic lung disease (CLD). Important outcomes included any CLD, death, death or moderate-severe CLD, pulmonary air leak syndrome, intestinal perforation, and moderate to severe neurodevelopmental impairment. RISK OF BIAS: We assessed risk of bias using the Cochrane RoB 1 tool. SYNTHESIS METHODS: We evaluated seven non-invasive respiratory support modes: nasal continuous positive airway pressure (CPAP); non-invasive positive pressure ventilation (NIPPV); biphasic positive airway pressure (BiPAP); high-flow nasal cannula (HFNC); non-invasive high-frequency oscillatory ventilation (NIHFV); non-invasive neurally adjusted ventilatory assist (NIV-NAVA); high nasal continuous positive airway pressure (H-CPAP). We used random-effects pairwise meta-analysis for direct comparisons and a Bayesian network meta-analysis to estimate network risk ratio (nRR) and 95% credible interval (95% CrI) for indirect and mixed comparisons across seven non-invasive respiratory support modes. We assessed the certainty of evidence using Confidence In Network Meta-Analysis specifically developed for network meta-analysis. INCLUDED STUDIES: We included 54 studies involving 6995 preterm infants. SYNTHESIS OF RESULTS: Treatment failure (48 studies, 6652 infants). NIPPV may result in a large reduction in treatment failure compared to CPAP (nRR 0.48, 95% CrI 0.36 to 0.62; low-certainty evidence) and HFNC (nRR 0.39, 95% CrI 0.26 to 0.57; low-certainty evidence). NIHFV likely results in a large reduction in treatment failure compared to CPAP (nRR 0.39, 95% CrI 0.26 to 0.58; moderate-certainty evidence) and may result in a large reduction in treatment failure compared to HFNC (nRR 0.32, 95% CrI 0.19 to 0.52; low-certainty evidence). For other comparisons, the evidence was very uncertain or there may have been little to no difference. Endotracheal ventilation (47 studies, 6459 infants). NIPPV may result in a large reduction in endotracheal ventilation compared to CPAP (nRR 0.51, 95% CrI 0.38 to 0.65; low-certainty evidence). NIHFV likely results in a large reduction in endotracheal ventilation compared to CPAP (nRR 0.38, 95% CrI 0.25 to 0.57; moderate-certainty evidence) and HFNC (nRR 0.34, 95% CrI 0.20 to 0.56; moderate-certainty evidence). For other comparisons, the evidence was very uncertain or there may have been little to no difference. Moderate to severe CLD (22 studies, 4895 infants). NIHFV may result in a large reduction in moderate to severe CLD compared to CPAP (nRR 0.64, 95% CrI 0.43 to 0.92; low-certainty evidence). For other comparisons, the evidence was very uncertain or there may have been little to no difference. The most common reasons for downgrading the certainty of evidence in the above analyses were within-study bias, imprecision, and heterogeneity. Sensitivity analysis (only studies with low risk of bias; findings similar to main analysis). NIPPV may result in a large reduction in treatment failure compared to CPAP (nRR 0.55, 95% CrI 0.31 to 0.88; low-certainty evidence) and HFNC (nRR 0.39, 95% CrI 0.17 to 0.81; low-certainty evidence). NIHFV results in a large reduction in treatment failure compared to CPAP (nRR 0.32, 95% CrI 0.14 to 0.70; high-certainty evidence) and HFNC (nRR 0.23, 95% CrI 0.08 to 0.58; high-certainty evidence). NIHFV likely results in a large reduction in endotracheal intubation compared to CPAP (nRR 0.33, 95% CrI 0.15 to 0.71; moderate-certainty evidence) and results in a large reduction in endotracheal intubation compared to HFNC (nRR 0.25, 95% CrI 0.08 to 0.66; high-certainty evidence). For other comparisons, the evidence is very uncertain or there may have been little to no difference. Stratified analysis 1. Analyses restricted to preterm infants 28 weeks' gestational age or greater were consistent with main analyses. For treatment failure, NIPPV may largely reduce risk compared to CPAP (nRR 0.44, 95% CrI 0.27 to 0.70; low-certainty evidence) and HFNC (nRR 0.47, 95% CrI 0.27 to 0.82; low-certainty evidence), and NIHFV may largely reduce the risk compared to CPAP (nRR 0.44, 95% CrI 0.27 to 0.70; low-certainty evidence) and HFNC (nRR 0.31, 95% CrI 0.17 to 0.54; low-certainty evidence). NIHFV likely results in a large reduction of treatment failure compared to BiPAP (nRR 0.35, 95% CrI 0.13 to 0.86; moderate-certainty evidence). For endotracheal ventilation, NIPPV may largely reduce the risk compared to HFNC (nRR 0.43, 95% CrI 0.24 to 0.79; low-certainty evidence) and NIHFV may largely reduce the risk compared to CPAP (nRR 0.44, 95% CrI 0.28 to 0.67; low-certainty evidence). NIHFV likely results in a large reduction of endotracheal ventilation compared to HFNC (nRR 0.29, 95% CrI 0.15 to 0.54; moderate-certainty evidence) and BiPAP (nRR 0.35, 95% CrI 0.14 to 0.84; moderate-certainty evidence). For the other comparisons, the evidence was very uncertain or there may have been little to no difference in critical outcomes. 2. Analyses restricted to preterm infants less than 28 weeks' gestational age: the evidence is very uncertain or there may have been little to no difference in any of the critical outcomes. However, very few studies and participants contributed to these analyses. Results of important outcomes are provided in the main review text. AUTHORS' CONCLUSIONS: NIPPV may reduce the risk of treatment failure or endotracheal ventilation compared to CPAP or HFNC, but may not reduce the risk of moderate to severe CLD. NIHFV likely reduces the risk of treatment failure and endotracheal ventilation, and may reduce the risk of moderate to severe CLD, compared to CPAP. More data are needed for extremely preterm infants under 28 weeks' gestational age, as they are at the highest risk of extubation failure and are currently under-represented in studies. Further research with matched mean airway pressure between different non-invasive respiratory support modes is necessary to ensure comparability and demonstrate that the benefits are due to the unique characteristics of these non-invasive respiratory support modes. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Protocol available via DOI: 10.1002/14651858.CD014509.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is marked by progressive lung scarring with no existing cure, emphasising the need for new therapeutic targets. Current evidence suggests that cyclic adenosine monophosphate (cAMP) mitigates lung fibroblast proliferation OBJECTIVE: To investigate the role of Epac1 in IPF progression. METHODS: We examined lung samples from IPF patients and controls, and from a bleomycin-induced mouse model of pulmonary fibrosis. The effects of Epac were analysed in knockout mice and through modulation using viral vectors. The Epac1-specific small compound inhibitor AM-001 was evaluated RESULTS: Increased Epac1 expression was observed in lung tissues from IPF patients, fibrotic fibroblasts and bleomycin-challenged mice. Genetic or pharmacological inhibition of Epac1 with AM-001 decreased proliferation in normal and IPF fibroblasts, and reduced expression of profibrotic markers such as α-smooth muscle actin, transforming growth factor-β/SMAD family member 2/3, and interleukin-6/signal transducer and activator of transcription 3 pathways. Epac1-specific inhibition consistently protected against bleomycin-induced lung injury and fibrosis, suggesting significant therapeutic potential. Global gene expression profiling indicated a reduced profibrotic gene signature and neddylation pathway components in Epac1-deficient fibroblasts and human-derived lung cells. Mechanistically, the protective effects may involve inhibiting the neddylation pathway and preventing neural precursor cell expressed, developmentally downregulated 8 (NEDD8) activation, which in turn reduces the degradation of forkhead box protein O3 by NEDD8. Additionally, these effects may be enhanced while also limiting the proliferation of lung-infiltrating monocytes. CONCLUSIONS: Our findings demonstrate that Epac1 regulates fibroblast activity in pulmonary fibrosis, and that targeting Epac1 with the pharmacological specific inhibitor AM-001 offers a promising therapeutic approach for treating IPF disease.

Diagnosing pulmonary embolism (PE) in patients with chronic obstructive pulmonary disease (COPD) exacerbation is challenging due to similarities in clinical symptoms. The aim of this study was to evaluate predictors of PE and to derive and validate a COPD-specific PE diagnostic strategy.A post-hoc analysis of the PEP trial, a prospective multicenter study of patients with COPD hospitalized with acutely worsening respiratory symptoms, was conducted. The outcome predicted was PE at admission. Univariable and multivariable analyses were conducted to evaluate predictors of PE. Receiver operating characteristic curves were computed to determine the most discriminant D-dimer cut-offs. The COPD-specific PE diagnostic strategy was externally validated in the independent SLICE trial cohort.A total of 734 patients were included. At admission, the prevalence of PE and/or proximal deep venous thrombosis (DVT) was 6.5% (95%CI 5.0-8.6%). A COPD-specific PE diagnostic strategy consisting of a 3-item score (type of COPD exacerbation, alternative diagnosis less likely than PE, and clinical signs of DVT) combined with D-dimer at specific cut-offs (1,000 μg/L if 0 score item and 500 μg/L if 1 or 2 score items) was derived. The overall diagnostic failure rate was 0.9% (95%CI 0.4-1.9%) and 392 patients (53.4%) would need imaging to rule out PE. The external validation showed comparable results.A COPD-specific PE diagnostic strategy was derived specifically for patients with COPD and acutely worsening respiratory symptoms. Further prospective validation of this diagnostic algorithm is needed prior to integrating it in clinical practice.