Assessing the effectiveness of inhalation therapy in patients with chronic airway diseases: A new digital measurement.

BACKGROUND: This study aimed to evaluate the effectiveness of inhalation therapy in patients with chronic airway diseases via the use of a new multiparametric inhalation assessment device. METHODS: A multiparametric inhalation evaluation device (PF810, UBREATH, Zhejiang, China) that could simulate common inhalation devices with 6 different levels (0-V) of resistance was used in this study. The device was considered suitable if the three parameters of peak inspiratory flow rate (PIFR), effective inspiratory time (EIT), and breath-hold time (BHT) after inspiration met the minimum requirements. RESULTS: A total of 4,559 tests were performed. The qualification rates of 0-V resistance gear from low to high were 3.38 % (I), 8.42 % (0), 15.31 % (II), 16.71 % (III), 20.27 % (IV), and 46.91 % (V). The COPD patients in the 3 experimental groups had the lowest percentages of isolates classified as resistant 0, III, and V, which were 5.65 %, 11.93 %, and 40.43 %, respectively. The lowest percentage was 39.67 % (V) for insufficient EIT and 18.40 % (V) for BHT less than 5 s after inspiration. The results of 149 subjects who had used the inhalation device showed that the VIE and EIT at 0 levels were significantly greater than those before training (Z= -5.651, -5.646, P < 0.001). The VIE and EIT at I-III and V significantly increased after training (all P < 0.05). CONCLUSIONS: Patients using portable inhaler devices do not always inhale with adequate flow patterns. The multiparametric inhalation assessment device may be useful in outpatient settings.

Adherence, Disease Control, and Misconceptions Related to the Use of Inhalation Therapy in Patients with Obstructive Pulmonary Diseases: A Cross-Sectional Study.

Background and Objectives: Inadequate treatment of asthma and chronic obstructive pulmonary disease (COPD) might have a negative impact on their progression. Inhalation therapy is the cornerstone of pharmacotherapy for these conditions. However, challenges such as low adherence, negative attitudes, and misconceptions about inhaled medications still persist, impeding effective disease management. This study aimed to evaluate adherence, ascertain the level of disease control in asthma and COPD, explore potential misconceptions surrounding inhalation therapy among patients with obstructive lung diseases and the general population in Vojvodina, and evaluate the reliability of newly developed questionnaires employed in the study. Materials and Methods: This cross-sectional study utilized a battery of questionnaires encompassing sociodemographic data, the Asthma Control Test (ACT), the COPD Assessment Test (CAT), along with two novel questionnaires-one for assessing adherence and another for analyzing attitudes toward inhalation therapy. Statistical analyses were conducted using SPSS software, version 25.0. Results: The average ACT score among patients with asthma was 17.31, while it was 19.09 for the CAT questionnaire among COPD patients. The composite score on the newly developed adherence assessment questionnaire was 2.27, exhibiting a reliability coefficient lower than recommended (α = 0.468). Significant statistical differences emerged among sample subgroups regarding attitudes and misconceptions toward inhalation therapy. The reliability coefficient for this questionnaire was deemed satisfactory (α = 0.767). Conclusions: Adherence rates were notably suboptimal in both subgroups of the studied population. The disease control levels were higher among asthma patients, while they exhibited less prevalent misconceptions regarding inhalation therapy compared to COPD patients and the healthy population.

High-Flow Nasal Cannula Versus Noninvasive Ventilation as Initial Treatment in Acute Hypoxia: A Propensity Score-Matched Study.

IMPORTANCE: Patients presenting to the emergency department (ED) with hypoxemia often have mixed or uncertain causes of respiratory failure. The optimal treatment for such patients is unclear. Both high-flow nasal cannula (HFNC) and noninvasive ventilation (NIV) are used. OBJECTIVES: We sought to compare the effectiveness of initial treatment with HFNC versus NIV for acute hypoxemic respiratory failure. DESIGN SETTING AND PARTICIPANTS: We conducted a retrospective cohort study of patients with acute hypoxemic respiratory failure treated with HFNC or NIV within 24 hours of arrival to the University of Michigan adult ED from January 2018 to December 2022. We matched patients 1:1 using a propensity score for odds of receiving NIV. MAIN OUTCOMES AND MEASURES: The primary outcome was major adverse pulmonary events (28-d mortality, ventilator-free days, noninvasive respiratory support hours) calculated using a win ratio. RESULTS: A total of 1154 patients were included. Seven hundred twenty-six (62.9%) received HFNC and 428 (37.1%) received NIV. We propensity score matched 668 of 1154 (57.9%) patients. Patients on NIV versus HFNC had lower 28-day mortality (16.5% vs. 23.4%, p = 0.033) and required noninvasive treatment for fewer hours (median 7.5 vs. 13.5, p < 0.001), but had no difference in ventilator-free days (median [interquartile range]: 28 [26, 28] vs. 28 [10.5, 28], p = 0.199). Win ratio for composite major adverse pulmonary events favored NIV (1.38; 95% CI, 1.15-1.65; p < 0.001). CONCLUSIONS AND RELEVANCE: In this observational study of patients with acute hypoxemic respiratory failure, initial treatment with NIV compared with HFNC was associated with lower mortality and fewer composite major pulmonary adverse events calculated using a win ratio. These findings underscore the need for randomized controlled trials to further understand the impact of noninvasive respiratory support strategies.

Effects of a lower versus a higher oxygenation target in intensive care unit patients with chronic obstructive pulmonary disease and acute hypoxaemic respiratory failure: a subgroup analysis of a randomised clinical trial.

Background: Oxygen supplementation is ubiquitous in intensive care unit (ICU) patients with chronic obstructive pulmonary disease (COPD) and acute hypoxaemia, but the optimal oxygenation target has not been established. Methods: This was a pre-planned subgroup analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) trial, which allocated patients with acute hypoxaemia to a lower oxygenation target (partial pressure of arterial oxygen [Pao2] of 8 kPa) vs a higher target (Pao2 of 12 kPa) during ICU admission, for up to 90 days; the allocation was stratified for presence or absence of COPD. Here, we report key outcomes for patients with COPD. Results: The HOT-ICU trial enrolled 2928 patients of whom 563 had COPD; 277 were allocated to the lower and 286 to the higher oxygenation group. After allocation, the median Pao2 was 9.1 kPa (inter-quartile range 8.7-9.9) in the lower group vs 12.1 kPa (11.2-12.9) in the higher group. Data for arterial carbon dioxide (Paco2) were available for 497 patients (88%) with no between-group difference in time-weighted average; median Paco2 6.0 kPa (5.2-7.2) in the lower group vs 6.2 kPa (5.4-7.3) in the higher group. At 90 days, 122/277 patients (44%) in the lower oxygenation group had died vs 132/285 patients (46%) in the higher (relative risk 0.98; 95% confidence interval 0.82-1.17; P=0.67). No statistically significant differences were found in any secondary outcome. Conclusions: In ICU patients with COPD and acute hypoxaemia, a lower vs a higher oxygenation target did not reduce mortality. There were no between-group differences in Paco2 or in secondary outcomes. Clinical trial registration: NCT03174002, EudraCT number 2017-000632-34.

High-flow nasal cannula during pulmonary rehabilitation for people with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an increasingly concerning global public health issue due to its high burden of morbidity and mortality. Pulmonary rehabilitation (PR) is a comprehensive intervention to improve patients' physical and psychological conditions, commonly involving oxygen supplementation. The potential benefits of high-flow nasal cannula (HFNC) have recently sparked interest as oxygen therapy. In this context, this study aims to assess the effects of HFNC during the exercise training component of a PR program in people with COPD. METHODS: Systematic review (CRD42022330929). We included randomised controlled trials (RCTs), including crossover RCTs with adults with stable COPD. We included trials using oxygen therapy with HFNC during the exercise training component of a PR programme. PRIMARY OUTCOMES: disease-specific health-related quality of life (HRQoL), exercise capacity (EC) and adverse events. SECONDARY OUTCOMES: treatment adherence, breathlessness and future exacerbations. RESULTS: We included five studies with 300 participants with moderate to severe COPD. The certainty of the evidence was primarily low or very low for all outcomes of interest due to risk of bias, inconsistency or imprecision. HFNC has little to no difference in HRQoL (4 studies, 129 participants, MD 0.17, 95% CI -1.20 to 1.54; I2 50%). HFNC may result in little to no difference in EC (3 studies, 212 participants, mean difference 18.73, 95% CI -20.49 to 28.94; I2 56%), and we are uncertain about the effect of HFNC on breathlessness (4 studies; 244 participants, MD of -0.07, 95% CI -0.4 to 0.26; I2 63%). Only one study with 44 participants reported a participant's withdrawal because of progressive dyspnoea during lower limb exercise. CONCLUSIONS: We are uncertain about the effect of HFNC during the exercise component of a PR programme in HRQoL, EC or dyspnoea compared to usual care or conventional supplementary oxygen. Non-domiciliary oxygen patients showed improvements in HRQoL, EC and dyspnoea.

Asthma patients' and physicians' perspectives on the burden and management of asthma: Post-hoc analysis of APPaRENT 1 and 2 to assess predictors of treatment adherence.

INTRODUCTION: Patient adherence to maintenance medication is critical for improving clinical outcomes in asthma and is a recommended guiding factor for treatment strategy. Previously, the APPaRENT studies assessed patient and physician perspectives on asthma care; here, a post-hoc analysis aimed to identify patient factors associated with good adherence and treatment prescription patterns. METHODS: APPaRENT 1 and 2 were cross-sectional online surveys of 2866 adults with asthma and 1883 physicians across Argentina, Australia, Brazil, Canada, China, France, Italy, Mexico, and the Philippines in 2020-2021. Combined data assessed adherence to maintenance medication, treatment goals, use of asthma action plans, and physician treatment patterns and preferences. Multivariable logistic regression models assessed associations between patient characteristics and both treatment prescription (by physicians) and patient treatment adherence. RESULTS: Patient and physician assessments of treatment goals and adherence differed, as did reporting of short-acting ß2-agonist (SABA) prescriptions alongside maintenance and reliever therapy (MART). Older age and greater patient-reported severity and reliever use were associated with better adherence. Patient-reported prescription of SABA with MART was associated with household smoking, severe or poorly controlled asthma, and living in China or the Philippines. CONCLUSIONS: Results revealed an important disconnect between patient and physician treatment goals and treatment adherence, suggesting that strategies for improving patient adherence to maintenance medication are needed, focusing on younger patients with milder disease. High reliever use despite good adherence may indicate poor disease control. Personalised care considering patient characteristics alongside physician training in motivational communication and shared decision-making could improve patient management and outcomes.

[Incidence of pressure injuries associated with oxygen therapy devices in the neonatal intensive care unit]. / Incidencia de lesiones por presión asociadas a dispositivos de oxigenoterapia en la unidad de cuidados intensivos neonatales.

OBJECTIVE: The administration of oxygen therapy (O2) in neonatal intensive care units (NICU) increases the risk of developing pressure injuries (PBI). The aims of the study were to describe the incidence of PBI associated with O2 devices in the NICU, to identify, analyze and relate risk factors and the application of their preventive measures. METHODS: A retrospective, observational and analytical study of hospitalized neonates who developed PPL secondary to O2 devices in the NICU of the Miguel Servet University Hospital of Zaragoza was carried out. Socio-demographical, clinical, type of cot, humidity, temperature, type of oxygen therapy, ventilation mode, device and presence of ulcer (number, degree, location), and preventive measures were recorded. The study was approved by the Research Ethics Committee of the Autonomous Community of Aragon. Statistical analysis was performed using Jamovi 2.3.13®. RESULTS: A total of 191 neonates were included, of whom 158 (82.7%) received O2. Of those who received oxygen therapy, 64.10% (25) were infants, mean total age 5.20±8.46 days and mean weight 1,460.03±777.57 grams. 24.68% presented with device-associated PPL, with a mean number of days of admission at the time of onset of 3.98±5.03 days. 94.74% (36) of the lesions were grade I and 84.62% (33) were located in the nasal septum. CONCLUSIONS: The incidence of pressure injuries associated with different oxygen therapy devices increases with decreasing gestational age. The risk increases with hospital stay, with the presence of medical devices, in particular non-invasive mechanical ventilation, being the main causal relationship.

OBJETIVO: La administración de oxigenoterapia en las unidades de cuidados intensivos neonatales (UCIN) supone un aumento del riesgo de desarrollar lesiones por presión (LPP). Los objetivos de este trabajo fueron describir la incidencia de LPP asociadas a dispositivos de oxigenoterapia, así como identificar, analizar y relacionar los factores de riesgo y sus medidas preventivas. METODOS: Se realizó un estudio retrospectivo, observacional y analítico de neonatos hospitalizados que desarrollaran una LPP secundaria a dispositivos de O2 en la UCIN del Hospital Universitario Miguel Servet de Zaragoza. Las variables registradas fueron las sociodemográficas, las clínicas, el tipo de cuna, la humedad, la temperatura, el tipo de oxigenoterapia, el tipo de ventilación, el dispositivo utilizado, la presencia de úlcera (número, grado, localización) y las medidas preventivas aplicadas. El estudio fue aprobado por el Comité de Ética de la Investigación de la Comunidad Autónoma de Aragón. El análisis estadístico se realizó mediante Jamovi 2.3.13®. RESULTADOS: Se incluyeron 191 neonatos, de los cuales 158 (82,7%) recibieron oxigenoterapia. El 64,10% de ellos fueron niños, la media de edad fue de 5,20±8,46 días y la de peso de 1.460,0±777,57 gramos. El 24,68% presentaron LPP asociada a dispositivo, con una media de días de ingreso en el momento de la aparición de 3,98±5,03 días. El 94,74% de las lesiones fueron de grado I y el 84,62% se localizaron en tabique nasal. CONCLUSIONES: La incidencia de LPP asociada a los diferentes dispositivos de oxigenoterapia aumenta a medida que disminuye la edad gestacional. El riesgo aumenta con la estancia hospitalaria, siendo la presencia de dispositivos médicos, en particular la ventilación mecánica no invasiva, la principal causa.

Determinants of physical quality of life in patients with chronic thromboembolic pulmonary hypertension after treatment: Insights from invasive exercise stress test.

BACKGROUND: Impaired quality of life (QoL) is prevalent among patients with chronic thromboembolic pulmonary hypertension (CTEPH) despite improved survival due to medical advances. We clarified the physical QoL of patients with CTEPH with mildly elevated pulmonary hemodynamics and evaluated its determinants using a database of patients with CTEPH evaluated for hemodynamics during exercise. METHODS: The QoL was measured in 144 patients with CTEPH (age, 66 (58-73) years; men/women, 48/96) with mildly elevated mean pulmonary artery pressure (<30 mm Hg) at rest after treatment with balloon pulmonary angioplasty and/or pulmonary endarterectomy using the Short-Form 36 (SF-36) questionnaire. The enrolled patients were divided into 2 groups: physical component summary (PCS) scores in the SF-36 over 50 as PCS-good and those under 50 as PCS-poor. RESULTS: The median PCS in SF-36 score was 43.4 (IQR 32.4-49.5) points. The PCS-poor group (n = 110) was older and had lower exercise capacity and SaO2 during exercise. PCS scores were correlated with 6-minute walk distance (rs=0.40, p < 0.001), quadriceps strength (rs=0.34, p < 0.001), peak VO2 (rs=0.31, p < 0.001), SaO2 at rest (rs=0.35, p < 0.001) and peak exercise (rs=0.33, p < 0.001), home oxygen therapy usage (rs=-0.28, p = 0.001), and pulmonary vascular resistance at peak exercise (rs=-0.26, p = 0.002). CONCLUSIONS: The impairment of physical QoL was common in patients with CTEPH with improved hemodynamics; exercise capacity, hypoxemia, and hemodynamic status during exercise were related to the physical QoL.

Selective Replacement of Cholesterol with Cationic Amphiphilic Drugs Enables the Design of Lipid Nanoparticles with Improved RNA Delivery.

The delivery of RNA across biological barriers can be achieved by encapsulation in lipid nanoparticles (LNPs). Cationic amphiphilic drugs (CADs) are pharmacologically diverse compounds with ionizable lipid-like features. In this work, we applied CADs as a fifth component of state-of-the-art LNPs via microfluidic mixing. Improved cytosolic delivery of both siRNA and mRNA was achieved by partly replacing the cholesterol fraction of LNPs with CADs. The LNPs could cross the mucus layer in a mucus-producing air-liquid interface model of human primary bronchial epithelial cells following nebulization. Moreover, CAD-LNPs demonstrated improved epithelial and endothelial targeting following intranasal administration in mice, without a marked pro-inflammatory signature. Importantly, quantification of the CAD-LNP molar composition, as demonstrated for nortriptyline, revealed a gradual leakage of the CAD from the formulation during LNP dialysis. Altogether, these data suggest that the addition of a CAD prior to the rapid mixing process might have an impact on the composition, structure, and performance of LNPs.

Novel inhalation therapy in pulmonary fibrosis: principles, applications and prospects.

Pulmonary fibrosis (PF) threatens millions of people worldwide with its irreversible progression. Although the underlying pathogenesis of PF is not fully understood, there is evidence to suggest that the disease can be blocked at various stages. Inhalation therapy has been applied for lung diseases such as asthma and chronic obstructive pulmonary disease, and its application for treating PF is currently under consideration. New techniques in inhalation therapy, such as the application of microparticles and nanoparticles, traditional Chinese medicine monomers, gene therapy, inhibitors, or agonists of signaling pathways, extracellular vesicle interventions, and other specific drugs, are effective in treating PF. However, the safety and effectiveness of these therapeutic techniques are influenced by the properties of inhaled particles, biological and pathological barriers, and the type of inhalation device used. This review provides a comprehensive overview of the pharmacological, pharmaceutical, technical, preclinical, and clinical experimental aspects of novel inhalation therapy for treating PF and focus on therapeutic methods that significantly improve existing technologies or expand the range of drugs that can be administered via inhalation. Although inhalation therapy for PF has some limitations, the advantages are significant, and further research and innovation about new inhalation techniques and drugs are encouraged.

Respiratory Support After Extubation in Children With Pediatric ARDS.

BACKGROUND: Postextubation respiratory support in pediatric ARDS may be used to support the recovering respiratory system and promote timely, successful liberation from mechanical ventilation. This study's aims were to (1) describe the use of postextubation respiratory support in pediatric ARDS from the time of extubation to hospital discharge, (2) identify potential risk factors for postextubation respiratory support, and (3) provide preliminary data for future larger studies. METHODS: This pilot single-center prospective cohort study recruited subjects with pediatric ARDS. Subjects' respiratory status up to hospital discharge, the use of postextubation respiratory support, and how it changed over time were recorded. Analysis was performed comparing subjects who received postextubation respiratory support versus those who did not and compared its use among pediatric ARDS severity categories. Multivariable logistic regression was used to determine variables associated with the use of postextubation respiratory support and included oxygenation index (OI), ventilator duration, and weight. RESULTS: Seventy-three subjects with pediatric ARDS, with median age and OI of 4 (0.6-10.5) y and 7.3 (4.9-12.7), respectively, were analyzed. Postextubation respiratory support was provided to 54/73 (74%) subjects: 28/45 (62.2%), 19/21 (90.5%), and 7/7 (100%) for mild, moderate, and severe pediatric ARDS, respectively, (P = .01). OI and mechanical ventilation duration were higher in subjects who received postextubation respiratory support (8.7 [5.4-14] vs 4.6 [3.7-7], P < .001 and 10 [7-17] d vs 4 [2-7] d, P < .001) compared to those who did not. At hospital discharge, 12/67 (18.2%) survivors received home respiratory support (6 subjects died prior to hospital discharge). In the multivariable model, ventilator duration (adjusted odds ratio 1.3 [95% CI 1.0-1.7], P = .050) and weight (adjusted odds ratio 0.95 [95% CI 0.91-0.99], P = .02) were associated with the use of postextubation respiratory support. CONCLUSIONS: The majority of intubated subjects with pediatric ARDS received respiratory support postextubation, and a substantial proportion continued to require it up to hospital discharge.

Natural Products-Based Inhaled Formulations for Treating Pulmonary Diseases.

Given the unique physiological and pathological characteristics of the lung, the direct, inhalable route is more conducive to pulmonary drug delivery and disease control than traditional systemic drug delivery, significantly circumventing drug loss, off-target effects, systemic and organ toxicity, etc., and is widely regarded as the preferred regimen for pulmonary drug delivery. However, very few lung diseases are currently treated with the preferred inhaled formulations, such as asthma, chronic obstructive pulmonary disease and pulmonary hypertension. And there is a lack of appropriate inhaled formulations for other critical lung diseases, such as lung cancer and pulmonary fibrosis, due to the fact that the physicochemical properties of the drugs and their pharmacokinetic profiles do not match the physiology of the lung, and conventional inhalation devices are unable to deliver them to the specific parts of the lung. Phytochemicals of natural origin, due to their wide availability and clear safety profile, hold great promise for the preparation of inhalable formulations to improve the current dilemma in the treatment of lung diseases. In particular, the preparation of inhalable formulations based on nano- and microparticulate carriers for drug delivery to deep lung tissues, which overcome the shortcomings of conventional inhalation therapies while targeting the drug activity directly to a specific part of the lung, may be the best approach to change the current dilemma of lung disease treatment. In this review, we discuss recent advances in nano- and micron-carrier-based inhalation formulations for the delivery of natural products for the treatment of pulmonary diseases, which may represent an opportunity for practical clinical translation of natural products.

Inhalation Delivery of Interferon-λ-Loaded Pulmonary Surfactant Nanoparticles Induces Rapid Antiviral Immune Responses in the Lung.

The interferon-λ (IFN-λ)-regulated innate immune responses in the airway expand our understanding toward antiviral strategies against influenza A virus (IAV). The application of IFN-λ as mucosal antiviral therapeutic is still challenging, and advanced research will be necessary to achieve more efficient delivery of recombinant IFN-λs to the damaged respiratory mucosa. In this study, we examine the capability of IFN-λ to stimulate the innate immune response, promoting the swift elimination of IAV in the lungs. Additionally, we develop IFN-λ-loaded nanoparticles incorporated into pulmonary surfactant for inhalation therapy aimed at treating lung infections caused by IAV. We found that inhaled delivery of IFNλ-PSNPs significantly restricted IAV replication in the lungs from 3 days after infection (dpi), and IAV-caused lung histopathologic findings were completely improved in response to IFNλ-PSNPs. More significant and rapid attenuation of viral RNA was observed in the lung of mice with inhaled delivery of IFNλ-PSNPs compared to mice with recombinant IFN-λs. Inhalation treatment of IFNλ-PSNPs to IAV-infected mice can result in the increase of monocyte frequency in concert with restoration of T and B cells composition. Furthermore, the transcriptional profiles of monocytes shifted toward heightened IFN responses following IFNλ-PSNP treatment. These results imply that IFN-λ could serve as a robust inducer of innate immunity in the lungs against IAV infection, and inhalation of IFN-λs encapsulated in PSNPs effectively resolves lung infections caused by IAV through rapid viral clearance. PSNPs facilitated improved delivery of IFN-λs to the lungs, triggering potent antiviral immune responses upon IAV infection onset.

Obesity as a Risk Factor for Complications and Mortality in Individuals with SARS-CoV-2: A Systematic Review.

This systematic review aimed to analyze the available studies that identified overweight and/or obesity as a risk factor for mortality, use of respiratory support, and changes in biochemical markers in adults hospitalized with SARS-CoV-2. The PubMed, Web of Science, and Scopus databases were searched using PRISMA guidelines until January 2024. The protocol was registered with PROSPERO (code: CRD42024501551). Of the 473 articles, only 8 met the inclusion criteria (e.g., adult individuals aged 18 or over diagnosed with COVID-19 individuals with overweight and/or obesity). In addition, the Downs and Black tool was used to assess the quality of the studies. The studies analyzed totaled 9782 adults hospitalized for COVID-19, indicating that overweight and obesity are present in more than half of adults. Diseases such as diabetes mellitus and hypertension are more prevalent in adults with obesity. The systematic review also highlighted that a higher incidence of respiratory support is related to a higher incidence of hospitalization in intensive care units and that adults with overweight and obesity have a higher risk of mortality from COVID-19. Biochemical markers such as procalcitinin, C-reactive protein, and interleukin-6 are associated with the severity of COVID-19 infection. This systematic review exposed overweight and/or obesity as a risk factor for worse COVID-19 disease, as well as for the need for intensive care, respiratory support, mortality, and changes in essential blood markers.

Evaluating ß2-agonists as siRNA delivery adjuvants for pulmonary surfactant-coated nanogel inhalation therapy.

The lung is an attractive target organ for inhalation of RNA therapeutics, such as small interfering RNA (siRNA). However, clinical translation of siRNA drugs for application in the lung is hampered by many extra- and intracellular barriers. We previously developed hybrid nanoparticles consisting of an siRNA-loaded nanosized hydrogel (nanogel) core coated with Curosurf®, a clinically used pulmonary surfactant. The surfactant shell was shown to markedly improve particle stability and promote intracellular siRNA delivery, both in vitro and in vivo. However, the full potential of siRNA nanocarriers is typically not reached as they are rapidly trafficked towards lysosomes for degradation and only a fraction of the internalized siRNA cargo is able to escape into the cytosol. We recently reported on the repurposing of widely applied cationic amphiphilic drugs (CADs) as siRNA delivery enhancers. Due to their physicochemical properties, CADs passively accumulate in the (endo)lysosomal compartment causing a transient permeabilization of the lysosomal membrane, which facilitates cytosolic drug delivery. In this work, we assessed a selection of cationic amphiphilic ß2-agonists (i.e., salbutamol, formoterol, salmeterol and indacaterol) for their ability to enhance siRNA delivery in a lung epithelial and macrophage cell line. These drugs are widely used in the clinic for their bronchodilating effect in obstructive lung disease. As opposed to the least hydrophobic drugs salbutamol and formoterol, the more hydrophobic long-acting ß2-agonist (LABA) salmeterol promoted siRNA delivery in both cell types for both uncoated and surfactant-coated nanogels, whereas indacaterol showed this effect solely in lung epithelial cells. Our results demonstrate the potential of both salmeterol and indacaterol to be repurposed as adjuvants for nanocarrier-mediated siRNA delivery to the lung, which could provide opportunities for drug combination therapy.

Physiological effect of high flow oxygen therapy measured by electrical impedance tomography in single-lung transplantation.

In patients with chronic obstructive pulmonary disease (COPD), single lung transplantation (SLT) is sometimes performed as an alternative to bilateral lung transplantation due to limited organ availability. However, the postoperative management of SLT presents challenges, including complications related to the distinct compliance of each lung. This case report presents the case of a 65-year-old male patient who underwent SLT and was in the weaning period from mechanical ventilation. High-flow oxygen therapy (HFOT) was administered, and the physiological effects were measured using electrical impedance tomography (EIT). The results demonstrated that the application of HFOT increased air trapping and overdistention in the native lung without benefiting the transplanted lung. HFOT through a tracheostomy tube or nasal cannula resulted in a more heterogeneous distribution of ventilation, with increased end expiratory lung impedance, prolonged expiratory time constants, and an increase in silent spaces. The drop in tidal impedance after applying HFOT did not indicate hypoventilation but rather overdistention and air trapping in the native lung, while the transplanted lung showed evidence of hypoventilation. These findings suggest that HFOT may not be beneficial for SLT patients and could potentially worsen outcomes. However, due to the limited scope of this case report, further prospective studies with larger patient cohorts are needed to confirm these results.

En pacientes con enfermedad pulmonar obstructiva crónica (EPOC), el trasplante pulmonar unilateral (SLT, por sus siglas en inglés) se realiza como alternativa a la disponibilidad limitada de donantes para el trasplante pulmonar bilateral. Sin embargo, el manejo postoperatorio del SLT presenta desafíos, incluyendo complicaciones relacionadas con la distinta complacencia de cada pulmón. Este reporte presenta el caso de un paciente varón de 65 años que fue sometido a un SLT y se encontraba en el proceso de destete de la ventilación mecánica. Se administró terapia de oxígeno de alto flujo (HFOT, por sus siglas en inglés) y se midieron los efectos fisiológicos utilizando la tomografía de impedancia eléctrica (EIT, por sus siglas en inglés). Los resultados demostraron que la aplicación de HFOT aumentó la retención de aire y la hiperinflación en el pulmón nativo sin beneficiar al pulmón trasplantado. Tanto la HFOT a través de un tubo de traqueostomía como a través de cánula nasal resultaron en una distribución más heterogénea de la ventilación, con un aumento en la impedancia pulmonar al final de la espiración, prolongación de las constantes de tiempo espiratorias y un aumento en los espacios silentes. La disminución de la impedancia tidal después de aplicar HFOT no indicó hipoventilación, sino más bien hiperinsuflación y retención de gas en el pulmón nativo, mientras que el pulmón trasplantado mostró evidencia de hipoventilación. Estos hallazgos sugieren que el HFOT puede no ser beneficioso para los pacientes con SLT y podría empeorar los resultados. Sin embargo, debido al alcance limitado de este informe de caso, se necesitan estudios prospectivos con cohortes de pacientes más amplias para confirmar estos resultados.

Aerosol Plumes of Inhalers Used in COPD.

INTRODUCTION: The selection of inhaler device is of critical importance in chronic obstructive pulmonary disease (COPD) as the interaction between a patient's inhalation profile and the aerosol characteristics of an inhaler can affect drug delivery and lung deposition. This study assessed the in vitro aerosol characteristics of inhaler devices approved for the treatment of COPD, including a soft mist inhaler (SMI), pressurized metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs). METHODS: High-speed video recording was used to visualize and measure aerosol velocity and spray duration for nine different inhalers (one SMI, three pMDIs, and five DPIs), each containing dual or triple fixed-dose combinations of long-acting muscarinic receptor antagonists and long-acting ß2-agonists, with or without an inhaled corticosteroid. Measurements were taken in triplicate at experimental flow rates of 30, 60, and 90 l/min. Optimal flow rates were defined based on pharmacopoeial testing requirements: 30 l/min for pMDIs and SMIs, and the rate achieving a 4-kPa pressure drop against internal inhaler resistance for DPIs. Comparison of aerosol plumes was based on the experimental flow rates closest to the optimal flow rates. RESULTS: The Respimat SMI had the slowest plume velocity (0.99 m/s) and longest spray duration (1447 ms) compared with pMDIs (velocity: 3.65-5.09 m/s; duration: 227-270 ms) and DPIs (velocity: 1.43-4.60 m/s; duration: 60-757 ms). With increasing flow rates, SMI aerosol duration was unaffected, but velocity increased (maximum 2.63 m/s), pMDI aerosol velocity and duration were unaffected, and DPI aerosol velocity tended to increase, with a more variable impact on duration. CONCLUSIONS: Aerosol characteristics (velocity and duration of aerosol plume) vary by inhaler type. Plume velocity was lower and spray duration longer for the SMI compared with pMDIs and DPIs. Increasing experimental flow rate was associated with faster plume velocity for DPIs and the SMI, with no or variable impact on plume duration, whereas pMDI aerosol velocity and duration were unaffected by increasing flow rate.

Long-term cognitive and pulmonary functions following a lower versus a higher oxygenation target in the HOT-ICU and HOT-COVID trials: A protocol update.

BACKGROUND: The Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial was a multicentre, randomised, parallel-group trial of a lower oxygenation target (arterial partial pressure of oxygen [PaO2 ] = 8 kPa) versus a higher oxygenation target (PaO2 = 12 kPa) in adult ICU patients with acute hypoxaemic respiratory failure; the Handling Oxygenation Targets in coronavirus disease 2019 (HOT-COVID) tested the same oxygenation targets in patients with confirmed COVID-19. In this study, we aim to evaluate the long-term effects of these oxygenation targets on cognitive and pulmonary function. We hypothesise that a lower oxygenation target throughout the ICU stay may result in cognitive impairment, whereas a higher oxygenation target may result in impaired pulmonary function. METHODS: This is the updated protocol and statistical analysis plan of two pre-planned secondary outcomes, the long-term cognitive function, and long-term pulmonary function, in the HOT-ICU and HOT-COVID trials. Patients enrolled in both trials at selected Danish sites and surviving to 1 year after randomisation are eligible to participate. A Repeatable Battery for the Assessment of Neuropsychological Status score and a full-body plethysmography, including diffusion capacity for carbon monoxide, will be obtained. The last patient is expected to be included in the spring of 2024. CONCLUSION: This study will provide important information on the long-term effects of a lower versus a higher oxygenation target on long-term cognitive and pulmonary functions in adult ICU patients with acute hypoxaemic respiratory failure.

Enhancing Inhalation Drug Delivery: A Comparative Study and Design Optimization of a Novel Valved Holding Chamber.

This paper presents an innovative approach to the design optimization of valved holding chambers (VHCs), crucial devices for aerosol drug delivery. We present the design of an optimal cylindrical VHC body and introduce a novel valve based on particle impaction theory. The research combines computational simulations and physical experiments to assess the performance of various VHCs, with a special focus on the deposition patterns of medication particles within these devices. The methodology incorporates both experimental and simulation approaches to validate the reliability of the simulation. Emphasis is placed on the deposition patterns observed on the VHC walls and the classification of fine and large particles for salbutamol sulfate particles. The study reveals the superior efficacy of our valve design in separating particles compared to commercially available VHCs. In standard conditions, our valve design allows over 95% of particles under 7 µm to pass through while effectively filtering those larger than 8 µm. The optimized body design accomplishes a 60% particle mass flow fraction at the outlet and an average particle size reduction of 58.5%. When compared numerically in terms of size reduction, the optimal design outperforms the two commercially available VHCs selected. This study provides valuable insights into the optimization of VHC design, offering significant potential for improved aerosol drug delivery. Our findings demonstrate a new path forward for future studies, aiming to further optimize the design and performance of VHCs for enhanced pulmonary drug delivery.