Uncovering patterns of inhaler technique and reliever use: the value of objective, personalized data from a digital inhaler.

Electronic inhalers provide information about patterns of routine inhaler use. During a 12-week study, 360 asthma patients using albuterol Digihaler generated 53,083 inhaler events that were retrospectively analyzed. A total of 41,528 (78%) of the recorded inhalation events were suitable for flow analysis (having a PIF ≥ 18 L/min and <120 L/min). Median PIF, inhalation volume, inhalation duration, and time to PIF for these events steadily decreased between the first and last 10 days of the study, by 5.1%, 12.6%, 15.9%, and 6.4%, respectively. Continuous short-acting beta2-agonist (SABA) overuse, defined as ≥2 SABA inhalations/week throughout the study period, was seen in 29% (n = 104) of patients. Of 260 patients with ≥1 instance of acute short-term SABA overuse, 55 (21%) had a confirmed exacerbation. Electronic recording of real-life inhaler use can capture valuable, objective information that could inform disease management and clinical decision-making.

Comparison of inhaled salbutamol and salmeterol for the treatment of arterial hypoxaemia in anaesthetized horses: a randomized clinical trial.

OBJECTIVE: To compare the efficacy of inhaled salbutamol with salmeterol for the treatment of arterial hypoxaemia in anaesthetized horses. STUDY DESIGN: Prospective, randomized, clinical study. ANIMALS: A total of 108 client-owned horses (American Society of Anesthesiologists status I-V) anaesthetized for elective and emergency procedures. METHODS: Horses were premedicated with acepromazine [intramuscularly 0.1 mg kg-1 or intravenously (IV) 0.05 mg kg-1] and xylazine (0.6 mg kg-1 IV). Midazolam (0.06 mg kg-1 IV) and ketamine (2.2 mg kg-1 IV) were combined to induce anaesthesia, and isoflurane in oxygen/air mixture (inspired oxygen fraction 0.7) was used for maintenance of anaesthesia. Mechanical ventilation was initiated without delay using the following ventilator settings: tidal volume 10 mL kg-1, respiratory rate 8 breaths minute-1, inspiratory-to-expiratory time ratio 1:2, no positive end-expiratory pressure. If arterial blood gas analysis revealed PaO2 < 100 mmHg (13.3 kPa), the administration of either inhaled salbutamol (2 µg kg-1) or salmeterol (0.5 µg kg-1) was randomly assigned Blood gas analysis was repeated 15 and 30 minutes after treatment. The intervention was considered successful when PaO2 after treatment ≥ 1.2 × PaO2 before treatment (i.e. ≥20% increase). PaO2 at 15 and 30 minutes was compared between groups using Mann-Whitney U test; p < 0.05 was considered significant. RESULTS: Of the 108 horses, 60 were administered salbutamol, 65% and 60% responded successfully at 15 and 30 minutes, increasing their initial PaO2 by 38% and 44%, respectively. The other 48 horses were administered salmeterol, 35% responded successfully at 15 and 30 minutes, increasing their initial PaO2 by 3% and 4%, respectively. PaO2 was significantly higher after salbutamol than after salmeterol at 15 and 30 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: Using the described protocol, inhaled salbutamol was more effective than salmeterol in improving PaO2 in anaesthetized horses with value < 100 mmHg (13.3 kPa).

Retrospective study of the changes in dynamic compliance and ventilation/perfusion mismatch following salbutamol inhalation in hypoxaemic mechanically ventilated anaesthetized horses.

OBJECTIVE: To study the changes in dynamic compliance (Cdyn), ventilation/perfusion (V˙/ Q˙) mismatch and haemodynamic variables in hypoxaemic anaesthetized horses whose PaO2 increased following salbutamol inhalation. STUDY DESIGN: Retrospective, clinical, cohort study. ANIMALS: A group of 73 client-owned horses treated with salbutamol when PaO2 <100 mmHg (13.3 kPa) during anaesthesia. METHODS: Horses were divided into two groups: responders (R), where PaO2 after salbutamol ≥1.2 PaO2 before treatment (i.e. ≥20% increase), and non-responders (NR), where PaO2 after salbutamol <1.2 PaO2 before treatment. Demographic data and intraoperative variables before treatment were compared between R and NR. Cdyn, arterial to end-tidal carbon dioxide difference [P(a-E´)CO2], estimated ratio of dead space to tidal volume (est.VD/VT), estimated shunt fraction (F-shunt), heart rate, systolic, mean and diastolic arterial pressure and dobutamine requirements were compared before and after treatment within R and NR. For each variable, the difference (Δ) between values pre- and posttreatment was calculated and compared between groups R and NR. Numerical data were compared using univariate or bivariate analysis and categorical data were compared using chi-square test; p < 0.05. RESULTS: Of the 73 horses 50 were classified as R while 23 horses were classified as NR. There was no statistical difference between R and NR for demographic data or initial intraoperative variables except for body weight [R: 531 (170-715) kg, NR: 540 (420-914) kg]. While salbutamol did not alter Cdyn in either group, it significantly decreased P(a-E´)CO2, est.VD/VT and F-shunt in R only. ΔP(a-E´)CO2, Δest.VD/VT and ΔF-shunt were significantly greater in R (-17.8%, -19.0% and -24.1%, respectively) than in NR (11.5%, 6.6% and -0.3%, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: In hypoxaemic anaesthetized horses responding to inhaled salbutamol by a ≥1.2 increase in PaO2 no change in Cdyn was detected, but indicators of V˙/ Q˙ mismatch improved.

ß-Adrenergic Agonist-Induced Lactic Acidosis: A Case Report.

ß-Adrenergic agonist medications such as albuterol are the mainstay for treatment of patients with acute asthma exacerbations. Patients who present to the emergency department with severe symptoms are often treated with multiple albuterol doses in sequence to maximize the impact of the medications, relax bronchoconstriction, and relieve their breathlessness. Patients who present with acute dyspnea have numerous potential causes of hyperlactatemia and acidosis including an uncommonly recognized outcome of albuterol administration. This clinical case report outlines a scenario where a patient who was treated for an acute asthma exacerbation had rising lactate levels despite improving clinically. Causes of elevated lactate levels are discussed, particularly related to ß-adrenergic agonist use, and considerations for monitoring and withdrawal of albuterol administration are outlined.

Cognitive Effects of Three ß-Adrenoceptor Acting Drugs in Healthy Volunteers and Patients with Parkinson's Disease.

Background: Noradrenergic signaling declines in Parkinson's disease (PD) following locus coeruleus neurodegeneration. Epidemiologic studies demonstrate that ß-acting drugs slow PD progression. Objective: The primary objective was to compare the safety and effects of 3 ß-adrenoceptor (ß-AR) acting drugs on central nervous system (CNS) function after a single dose in healthy volunteers (HVs) and evaluate the effects of multiple doses of ß-AR acting drugs in HVs and PD-patients. Methods: In Part A, HVs received single doses of 32 mg salbutamol, 160µg clenbuterol, 60 mg pindolol and placebo administered in a randomized, 4-way cross-over study. In Part B (randomized cross-over) and Part C (parallel, 2:1 randomized), placebo and/or clenbuterol (20µg on Day 1, 40µg on Day 2, 80µg on Days 3-7) were administered. CNS functions were assessed using the NeuroCart test battery, including pupillometry, adaptive tracking and recall tests. Results: Twenty-seven HVs and 12 PD-patients completed the study. Clenbuterol improved and pindolol reduced the adaptive tracking and immediate verbal recall performance. Clenbuterol and salbutamol increased and pindolol decreased pupil-to-iris ratios. Clenbuterol was selected for Parts B and C. In Part B, clenbuterol significantly increased performance in adaptive tracking with a tendency toward improved performance in immediate and delayed verbal recall. In Part C trends toward improved performance in immediate and delayed verbal recall were observed in PD-patients. Typical cardiovascular peripheral ß2-AR effects were observed with clenbuterol. Conclusions: This study demonstrates the pro-cognitive effects of clenbuterol in HVs with similar trends in PD-patients. The mechanism of action is likely activation of ß2-ARs in the CNS.

Aims and Purpose of the Research:This research aimed to explore how three different drugs affect brain function. These drugs are salbutamol, clenbuterol, and pindolol and work in the brain by stimulating specific brain cells that can improve aspects like memory and coordination. The main question was to see how safe these drugs were and how they impact the brain function after one dose in healthy people, and after multiple doses in both healthy people and those with Parkinson's disease.Background of the Research:Parkinson's disease is a condition where brain cells start to die, which affects different areas of the brain, including movement function, as well as memory and attention. This research matters because finding drugs that affect the brain function could improve the lives of people with Parkinson's disease.Methods and Research Design:The study was conducted in three parts. In the first part, healthy volunteers took one dose of each of the three drugs­ salbutamol, clenbuterol, and pindolol­ as well as a placebo (a harmless pill that has no effect). The researchers tested the participants' brain functions using various tasks including memory tests and eye response measurements. In the second and third part, healthy people and people with Parkinson's disease took the drug that performed best in healthy volunteers for seven days.Results and Importance:In the first part, a single dose of clenbuterol was safe and improved memory and attentions tasks in healthy people, and therefore was chosen for further testing in the second and third part. In these parts, multiple doses of clenbuterol were safe and helped improve memory and attention tasks in healthy people, with similar positive trends seen in people with Parkinson's disease. The study suggests that clenbuterol might help improve brain function by activating specific receptors in the brain.These results are important because they suggest that clenbuterol could be a potential treatment to help improve brain function in people with Parkinson's disease. However, more research is needed to fully understand its effects and to confirm these findings.

Treatment Adherence and Health Status of Patients With COPD Under Treatment With Salmeterol/Fluticasone via the Elpenhaler® Device: The AHEAD Study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous progressive lung condition characterized by long-term respiratory symptoms and airflow limitation. Appropriate bronchodilation is the cornerstone of COPD treatment, leading to better health status as well as benefits in prognosis and mortality. METHODS: In the current open, noninterventional, observational study, 716 patients diagnosed with COPD of variable severity were administered a fixed-dose combination (FDC) of fluticasone propionate and salmeterol (500 + 50 mcg) through the Elpenhaler® device. The patients' adherence to treatment (based on the MMAS-8 [8-item Morisky Medication Adherence Scale]) and health status (based on the CCQ [Clinical COPD Questionnaire]) were assessed at the beginning of the study and at the end of the 3-month follow-up period. RESULTS: The mean ± SD MMAS-8 score at 1 and 3 months was 6.12 ± 1.89 and 6.45 ± 1.80, respectively, indicating medium adherence overall; however, there was a statistically significant increase of 0.33 units in the MMAS-8 score at the end of the follow-up (paired t-test p < 0.0001), suggestive of an improvement in adherence throughout the study. Higher adherence was associated with better health status at baseline, which further improved by the end of the follow-up. Moreover, we observed a statistically significant decrease of 1.07 points (p < 0.0001) in the mean CCQ total score from the baseline (CCQ score = 2.2 ± 1.00) until the end of the study follow-up (CCQ score = 1.13 ± 0.67). Similar conclusions were also drawn in the mean domain scores regarding symptoms (score equal to 1.36 ± 0.72, decrease by 1.18) as well as functional and mental state (scores equal to 0.86 ± 0.73 and 1.20 ± 0.88, decrease by 1.04 and 1.00, respectively, p < 0.0001). Similarly, when patients were stratified into subgroups with and without comorbidities, the former group showed an increase of 7% in the patients with medium to high adherence during the course of the study. In the same patient subgroup, there was a notable decrease in CCQ score by 1.18 points (p < 0.0001) during the study. CONCLUSIONS: The administration of FDC of fluticasone propionate and salmeterol, (500 + 50 mcg) via the Elpenhaler® device for COPD, resulted in a well-maintained or slight increase in treatment adherence and a subsequent benefit in health status, which further persisted after 3 months of treatment.

Integration of mucus and its impact within in vitro setups for inhaled drugs and formulations: Identifying the limits of simple vs. complex methodologies when studying drug dissolution and permeability.

Traditionally, developing inhaled drug formulations relied on trial and error, yet recent technological advancements have deepened the understanding of 'inhalation biopharmaceutics' i.e. the processes that occur to influence the rate and extent of drug exposure in the lungs. This knowledge has led to the development of new in vitro models that predict the in vivo behavior of drugs, facilitating the enhancement of existing formulation and the development of novel ones. Our prior research examined how simulated lung fluid (SLF) affects the solubility of inhaled drugs. Building on this, we aimed to explore drug dissolution and permeability in lung mucosa models containing mucus. Thus, the permeation of four active pharmaceutical ingredients (APIs), salbutamol sulphate (SS), tiotropium bromide (TioBr), formoterol fumarate (FF) and budesonide (BUD), was assayed in porcine mucus covered Calu-3 cell layers, cultivated at an air liquid interface (ALI) or submerged in a liquid covered (LC) culture system. Further analysis on BUD and FF involved their transport in a mucus-covered PAMPA system. Finally, their dissolution post-aerosolization from Symbicort® was compared using 'simple' Transwell and complex DissolvIt® apparatuses, alone or in presence of porcine mucus or polymer-lipid mucus simulant. The presence of porcine mucus impacted both permeability and dissolution of inhaled drugs. For instance, permeability of SS was reduced by a factor of ten in the Calu-3 ALI model while the permeability of BUD was reduced by factor of two in LC and ALI setups. The comparison of dissolution methodologies indicated that drug dissolution performance was highly dependent on the setup, observing decreased release efficiency and higher variability in Transwell system compared to DissolvIt®. Overall, results demonstrate that relatively simple methodologies can be used to discriminate between formulations in early phase drug product development. However, for more advanced stages complex methods are required. Crucially, it was clear that the impact of mucus and selection of its composition in in vitro testing of dissolution and permeability should not be neglected when developing drugs and formulations intended for inhalation.

Aerosol Delivery Efficiency With High-Flow Nasal Cannula Therapy in Neonatal, Pediatric, and Adult Nasal Upper-Airway and Lung Models.

BACKGROUND: High-flow nasal cannula (HFNC) systems employ different methods to provide aerosol to patients. This study compared delivery efficiency, particle size, and regional deposition of aerosolized bronchodilators during HFNC in neonatal, pediatric, and adult upper-airway and lung models between a proximal aerosol adapter and distal aerosol circuit chamber. METHODS: A filter was connected to the upper airway to a spontaneously breathing lung model. Albuterol was nebulized using the aerosol adapter and circuit at different clinical flow settings. The aerosol mass deposited in the upper airway and lung was quantified. Particle size was measured with a laser diffractometer. Regional deposition was assessed with a gamma camera at each nebulizer location and patient model with minimum flow settings. RESULTS: Inhaled lung doses ranged from 0.2-0.8% for neonates, 0.2-2.2% for the small child, and 0.5-5.2% for the adult models. Neonatal inhaled lung doses were not different between the aerosol circuit and adapter, but the aerosol circuit showed marginally greater lung doses in the pediatric and adult patient models. Impacted aerosols and condensation in the non-heated HFNC and aerosol delivery components contributed to the dispersion of coarse liquid droplets, high deposition (11-44%), and occlusion of the supine neonatal upper airway. In contrast, the upright pediatric and adult upper-airway models had minimal deposition (0.3-7.0%) and high fugitive losses (∼24%) from liquid droplets leaking out of the nose. The high impactive losses in the aerosol adapter (56%) were better contained than in the aerosol circuit, resulting in less cannula sputter (5% vs 22%), fewer fugitive losses (18% vs 24%), and smaller inhaled aerosols (5 µm vs 13 µm). CONCLUSIONS: The inhaled lung dose was low (1-5%) during HFNC. Approaches that streamline aerosol delivery are needed to provide safe and effective therapy to patients receiving aerosolized medications with this HFNC system.

Salbutamol Easyhaler provides non-inferior relief of methacholine induced bronchoconstriction in comparison to Ventoline Evohaler with spacer: A randomized trial.

BACKGROUND: Salbutamol is a cornerstone for relieving acute asthma symptoms, typically administered through a pressurized metered-dose inhaler (pMDI). Dry powder inhalers (DPIs) offer an alternative, but concerns exist whether DPIs provide an effective relief during an obstructive event. OBJECTIVE: We aimed to show non-inferiority of Salbutamol Easyhaler DPI compared to pMDI with spacer in treating methacholine-induced bronchoconstriction. Applicability of Budesonide-formoterol Easyhaler DPI as a reliever was also assessed. METHODS: This was a randomized, parallel-group trial in subjects sent to methacholine challenge (MC) test for asthma diagnostics. Participants with at least 20 % decrease in forced expiratory volume in 1 s (FEV1) were randomized to receive Salbutamol Easyhaler (2 × 200 µg), Ventoline Evohaler with spacer (4 × 100 µg) or Budesonide-formoterol Easyhaler (2 × 160/4.5 µg) as a reliever. The treatment was repeated if FEV1 did not recover to at least -10 % of baseline. RESULTS: 180 participants (69 % females, mean age 46 yrs [range 18-80], FEV1%pred 89.5 [62-142] %) completed the trial. Salbutamol Easyhaler was non-inferior to pMDI with spacer in acute relief of bronchoconstriction showing a -0.083 (95 % LCL -0.146) L FEV1 difference after the first dose and -0.032 (-0.071) L after the last dose. The differences in FEV1 between Budesonide-formoterol Easyhaler and Salbutamol pMDI with spacer were -0.163 (-0.225) L after the first and -0.092 (-0.131) L after the last dose. CONCLUSION: The study confirms non-inferiority of Salbutamol Easyhaler to Ventoline Evohaler with spacer in relieving acute bronchoconstriction, making Easyhaler a sustainable and safe reliever for MC test and supports its use during asthma attacks.

The Effect of Priming new Plastic Spacers with 20 Puffs Salbutamol on Bronchodilator Response in Asthmatic Children.

The static charge on the plastic body of spacers attracts drug aerosols, reducing the drug available for inhalation from plastic spacers. Some instructions exist to decrease the electric charge on plastic spacers, such as priming them with salbutamol (20 puffs) before use. This study investigates whether priming plastic spacer devices with this method can improve the bronchodilator test result. This study included children with stable mild to moderate asthma. All subjects underwent two pulmonary function tests to evaluate their bronchodilator response on separate days at 24-48 hours intervals. On each day, spirometry was performed at the baseline and 15 min after inhalation of four puffs of salbutamol (100 µg/puff) through either a primed or a new spacer. The change in forced expiratory volume in the first second (FEV1) after inhaling salbutamol was the primary outcome measure. When the patients used a new spacer, the mean baseline FEV1 (% predicted) and FEV1/FVC (forced vital capacity) were 89.56±11.95 and 86.17±6.87, respectively. However, the mean increase in FEV1 from the baseline was 10.87±8.99 in this group. On the other hand, with the primed spacer, the respective mean baseline FEV1 and FEV1/FVC values were 89.41±12.14 and 85.49±6.76, while it increased by 12.1±11.01 after salbutamol inhalation. There were no significant differences between the techniques regarding the variation in FEV1 before and after bronchodilator use via a new spacer or primed spacer. Priming new plastic spacers with 20 puffs of salbutamol did not cause additional bronchodilation in asthmatic children, suggesting this practice is inefficient in clinics.

Inhaled magnesium versus inhaled salbutamol in rescue treatment for moderate and severe asthma exacerbations in pediatric patients.

OBJECTIVE: To compare the effectiveness of inhaled Magnesium Sulfate associated with Salbutamol versus Inhaled Salbutamol alone in patients with moderate and severe asthma exacerbations. METHOD: Clinical, prospective and randomized study with patients between 3 and 14 years of age divided into two groups: one to receive inhaled salbutamol associated with magnesium sulfate (GSM), the other to receive inhaled salbutamol alone (GS). The sample consisted of 40 patients, 20 patients in each group. Severity was classified using the modified Wood-Downes score, with values between 4 and 7 classified as moderate and 8 or more classified as severe. RESULTS: Post-inhalation scores decreased both in patients who received salbutamol and magnesium and in those who received salbutamol alone, with no statistically significant difference between the groups. CONCLUSIONS: Despite the benefits when administered intravenously, inhalation of the drug alone or in combination did not reduce the severity of the exacerbation.

Changes in Peak Inspiratory Flow After Acute Bronchodilation: An Observational Study of Patients with Stable Chronic Obstructive Pulmonary Disease.

Introduction: Identifying factors influencing peak inspiratory flow (PIF) is essential for aerosol drug delivery in stable patients with chronic obstructive pulmonary disease. While a minimum PIF for dry powder inhalers (DPIs) is established, acute bronchodilator (BD) effects on PIF remain unknown. Materials and Methods: An inspiratory flow meter (In-Check™ DIAL) was used to measure PIF in stable patients during a 24-week observational cross-sectional study. Additionally, bronchodilator responsiveness (BDR) was determined using the In-Check DIAL device and spirometry. Patients received four puffs of albuterol, and pre- and post-BD PIF, forced expiratory volume in one second (FEV1), and forced vital capacity were measured. Sixty-three patients completed acute BDR data collection from July 31, 2019, to November 9, 2021. Primary endpoints were pre- and post-BD spirometry and PIF. Statistical analyses included PIF correlations with FEV1. BD change was assessed according to inhaler resistance and sex (subgroup analysis). Results: Median patient age was 64.8 years, 85.7% were non-Hispanic White, and 57.1% were female. The median increase in absolute PIF (In-Check DIAL) was 5.0 L/min, and the % PIF change was 8.9%. With albuterol, 57.1% experienced a PIF BD change >5.0%, whereas 49.2% experienced a change >10.0%. Similarly, 55.6% experienced an FEV1 BD change >5.0% and 28.6% had a >10.0% FEV1 BD change with albuterol. PIF was weakly correlated with FEV1 BD change (absolute; % PIF; r = 0.28 [p = 0.02]; r = 0.21 [p = 0.11]). Pre- and post-BD median PIF were 75.5 and 83.5 L/min for low-to-medium-resistance DPI and 45.0 and 52.0 L/min for high-resistance, respectively. The median increases in pre- and post-BD PIF were 9.0 L/min in males and 4.5 L/min in females. In contrast to when using the In-Check DIAL device, we observed no consistent bronchodilatory effects on PIF measured by spirometry. Conclusions: Using the In-Check DIAL device, ∼50% of patients experienced >10% PIF increase after acute BD, potentially enhancing medication lung deposition. Further research is required to understand PIF's impact on medication delivery. ClinicalTrials.gov Identifier: NCT04168775.

In silico investigation of inhalation condition impacts on hygroscopic growth and deposition of salbutamol sulphate in human airways.

The objective of this study is to explore the transport, size growth, and deposition of Salbutamol Sulphate (SS) using Computational Fluid Dynamics (CFD). A CT-based realistic model of human airways from the oral cavity to the 5th generation of the lung was utilized as the computational domain. Four Test Cases (TC) with varying temperature and relative humidity (RH) under two inspiratory waveforms were considered to completely evaluate the impact of inhalation conditions on particle growth. Salbutamol Sulphate (SS) is a ß2-adrenergic agonist and has been extensively used for asthma treatment. A monodispersed distribution of SS particles with an initial diameter of 167 nm was considered at the mouth inlet based on pharmaceutical data. Results indicated that inhalation of saturated/supersaturated air (RH>100%) leads to significant hygroscopic growth of SS particles with a factor of 10. In addition, the deposition efficiency of SS particles under the Quick and Deep (QD) inhalation profile was enhanced as the flow temperature and humidity increased. However, the implementation of Slow and Deep (SD) inspiratory waveform revealed that the same particle size growth is achieved in the respiratory system with lower deposition efficiency in the mouth-throat (less than 3%) and tracheobronchial airway (less than 2.18%). For the escaped particles form the right lung, in the SD waveform under TC 3, the maximum particle size distribution was for 600 nm particles with 25% probability. In the left lung, 30% of the particles were increased up to 950 nm in size. For the QD waveform in TC 3 and TC4, the most frequent particles were 800 nm with 36% probability. This holds practical significance in the context of deep lung delivery for asthmatic patients with enhanced deposition efficiency and large particle size. The findings of the present study can contribute to the development of targeted drug delivery strategies for the treatment of pulmonary diseases using hygroscopic dry powder formulations.

Albuterol-budesonide fixed-dose combination rescue inhaler for asthma: a plain language summary of the MANDALA study.

What is this summary about?This summary describes the results of a clinical study called MANDALA that was published in the New England Journal of Medicine in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both albuterol and budesonide in a single inhaler (known as albuterol-budesonide, AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.

Effect of Interrupting Heated Humidification on Nebulized Drug Delivery Efficiency, Temperature, and Absolute Humidity During Mechanical Ventilation: A Multi-Lab In Vitro Study.

Introduction: During mechanical ventilation (MV), inspired gases require heat and humidification. However, such conditions may be associated with reduced aerosol delivery efficiency. The practice of turning off heated humidification before nebulization and the impact of nebulization on humidity in a dry ventilator circuit remain topics of debate. This study aimed to assess the effect of turning off heated humidification on inhaled dose and humidity with nebulizer use during adult MV. Methods: A bronchodilator (albuterol) and two antibiotics (Colistimethate sodium and Amikacin sulfate) were nebulized with a vibrating mesh nebulizer placed at the humidifier inlet and in the inspiratory limb at the Y-piece. Additionally, albuterol was nebulized using a jet nebulizer in both placements. Aerosol particle size distribution was determined through a cascade impactor. Absolute humidity (AH) and temperature of inspired gases were determined with anemometer/hygrometers before, during, and after nebulization, before, during, and up to 60 minutes after interrupting active humidification. Aerosol collected on a filter distal to the endotracheal tube and on impactor stages were eluted and assayed by spectrophotometry. Results: The inhaled dose was greater when both nebulizers were placed at the humidifier inlet than the inspiratory limb at the Y-piece. Irrespective of the nebulizer types and placements, the inhaled dose either decreased or showed no significant change after the humidifier was turned off. The aerosol particle size ranged from 1.1 to 2.7 µm. With interruption of active humidification, humidity of inspired gas quickly dropped below recommended levels, and nebulization in dry ventilator circuit produced an AH between 10 and 20 mgH2O/L, lower than the recommended minimum of 30 mgH2O/L. Conclusion: Interrupting active humidification during MV before nebulization did not improve aerosol delivery efficiency for bronchodilator or antibiotics, but did reduce humidity below recommended levels.

The Effects of Inspiratory Flows, Inspiratory Pause, and Suction Catheter on Aerosol Drug Delivery with Vibrating Mesh Nebulizers During Mechanical Ventilation.

Background: Some experts recommend specific ventilator settings during nebulization for mechanically ventilated patients, such as inspiratory pause, high inspiratory to expiratory ratio, and so on. However, it is unclear whether those settings improve aerosol delivery. Thus, we aimed to evaluate the impact of ventilator settings on aerosol delivery during mechanical ventilation (MV). Methods: Salbutamol (5.0 mg/2.5 mL) was nebulized by a vibrating mesh nebulizer (VMN) in an adult MV model. VMN was placed at the inlet of humidifier and 15 cm away from the Y-piece of the inspiratory limb. Eight scenarios with different ventilator settings were compared with endotracheal tube (ETT) connecting 15 cm from the Y-piece, including tidal volumes of 6-8 mL/kg, respiratory rates of 12-20 breaths/min, inspiratory time of 1.0-2.5 seconds, inspiratory pause of 0-0.3 seconds, and bias flow of 3.5 L/min. In-line suction catheter was utilized in two scenarios. Delivered drug distal to the ETT was collected by a filter, and drug was assayed by an ultraviolet spectrophotometry (276 nm). Results: Compared to the use of inspiratory pause, the inhaled dose without inspiratory pause was either higher or similar across all ventilation settings. Inhaled dose was negatively correlated with inspiratory flow with VMN placed at 15 cm away from the Y-piece (rs = -0.68, p < 0.001) and at the inlet of humidifier (rs = -0.83, p < 0.001). The utilization of in-line suction catheter reduced inhaled dose, regardless of the ventilator settings and nebulizer placements. Conclusions: When VMN was placed at the inlet of humidifier, directly connecting the Y-piece to ETT without a suction catheter improved aerosol delivery. In this configuration, the inhaled dose increased as the inspiratory flow decreased, inspiratory pause had either no or a negative impact on aerosol delivery. The inhaled dose was greater with VMN placed at the inlet of humidifier than 15 cm away the Y-piece.

Reducing short-acting beta-agonist use in asthma: Impact of national incentives on prescribing practices in England and the findings from SENTINEL Plus early adopter sites.

Short-acting beta-agonist (SABA) over-use in asthma is harmful for patients and the environment. The Investment and Impact Fund (IIF) 2022/2023 financially rewarded English primary care networks that achieved specific targets, including reducing SABA over-use (RESP-02) and lowering the mean carbon footprint per salbutamol inhaler prescribed (ES-02). SENTINEL Plus is a co-designed quality improvement package that aims to improve asthma outcomes and reduce asthma's environmental impact by addressing SABA over-use. We investigated the impact of (i) the IIF incentives and (ii) SENTINEL Plus implementation on asthma prescribing. Using Openprescribing.net data, we demonstrate that IIF 2022-2023 had no significant impact on the total number of SABA prescribed in England (25,927,252 during 12-months pre- and 25,885,213 12-months post-IIF; 0.16% decrease; p=NS), but lower carbon footprint SABA inhaler use increased (Salamol™ prescribing increased from 5.1% to 19% of SABA prescriptions, p < 0.01). In contrast, SENTINEL Plus sites significantly reduced SABA prescribing post-implementation (5.43% decrease, p < 0.05).

Safety and Efficacy of 2.5 mg and 1.25 mg Nebulized Salbutamol Compared with Placebo on Transient Tachypnea of the Newborns: A Triple-Blind Phase II/III Parallel Randomized Controlled Trial.

Background: To evaluate the safety and efficacy of 2.5 and 1.25 mg nebulized salbutamol on Transient Tachypnea of the Newborn (TTN) compared with placebo. Methods: We conducted a triple-blind, phase II/III parallel randomized controlled trial in two university-affiliated hospitals with neonatal intensive care units. Newborns with a confirmed diagnosis of TTN, with gestational age >35 weeks and gestational weight >2 kg were included. Cases of asphyxia, meconium aspiration syndrome, and persistent pulmonary hypertension were excluded. Ninety eligible patients were randomly allocated in three intervention groups (2.5 mg salbutamol, 1.25 mg salbutamol, and placebo), and a single-dose nebulized product was prescribed 6 hours after the birth. Safety outcomes included postintervention tachycardia, hyperglycemia, hypokalemia, and changes in blood pressure. To evaluate the efficacy, the duration of postintervention tachypnea, TTN clinical score, and clinical and paraclinical respiratory indices were assessed. Parents, Outcome assessors, and data analyzer were blind to the intervention. Results: There was no adverse reaction, including tachycardia, hypokalemia, and jitteriness. Both groups of salbutamol recipients showed significant improvement regarding respiratory rate, TTN clinical score, and oxygenation indices compared with the placebo (p-values <0.001). Nonstatistically significant higher hospital stay was observed in the placebo group. Single 2.5 mg salbutamol nebulization showed a little better outcome than the dose of 1.25 mg, although we could not find statistical superiority. Conclusion: The newly applied single high dose of 2.5 mg nebulized salbutamol is safe in treating TTN and leads to notable faster improvement of respiratory status without any considerable adverse reaction. Registry code: IRCT20190328043133N1.

Hyperlacticaemia in children with status asthmaticus. The Stewart approach.

BACKGROUND: Patients with status asthmaticus (SA) frequently present with lactic acidosis (LA). Our goal is to identify the nature of this LA using the Stewart physicochemical model and to identify the independent factors associated with LA in children with SA. METHODS: Analytical study of a retrospective cohort using a nested case-control design. Twenty-eight episodes of SA in 24 children were included. Patients admitted to a paediatric intensive care unit (PICU) for SA over a 9-year period were recruited consecutively. Data were analysed using the Stewart model and the Strong Ion Calculator. Data were analysed using descriptive statistics and regression models were fitted within the general linear model. RESULTS: Hyperlacticaemia (Lact[mM/L] = 3.905 [95% CI = 3.018-4.792]) and acidosis (pH = 7.294 [95% CI = 7.241-7.339]) were observed in 18 episodes (15 patients; 62.5%). According to the Stewart model, acidosis was caused by a decrease in strong ion difference. Initially, pCO2 was high (pCO2[mmHg] = 45.806 [95% CI = 37.314-54.298]) but the net unmeasured ion (NUI) component was normal (NUI = -4,461 [95% CI = -3.51 to -5.412]), and neither changed significantly over the clinical course. There was no need to determine pyruvate, as the NUI was normal and the LA was type B (non-hypoxic, lactate/pyruvate < 25). We observed a correlation (P = .023) between LA and intramuscular epinephrine administered on arrival at hospital, but not between LA and the cumulative dose of nebulized salbutamol. CONCLUSIONS: Most patients with SA presented LA. The Stewart model confirmed that LA is not hypoxic, probably due to sympathomimetic-related glycolysis.

The carbon footprint of as-needed budesonide/formoterol in mild asthma: a post hoc analysis.

INTRODUCTION: The use of pressurised metered-dose inhalers (pMDIs) and asthma exacerbations necessitating healthcare reviews contribute substantially to the global carbon footprint of healthcare. It is possible that a reduction in carbon footprint could be achieved by switching patients with mild asthma from salbutamol pMDI reliever-based therapy to inhaled corticosteroid-formoterol dry powder inhaler (DPI) reliever therapy, as recommended by the Global Initiative for Asthma. METHODS: This post hoc analysis included all 668 adult participants in the Novel START trial, who were randomised 1:1:1 to treatment with as-needed budesonide/formoterol DPI, as-needed salbutamol pMDI or maintenance budesonide DPI plus as-needed salbutamol pMDI. The primary outcome was carbon footprint of asthma management, expressed as kilograms of carbon dioxide equivalent emissions (kgCO2e) per person-year. Secondary outcomes explored the effect of baseline symptom control and adherence (maintenance budesonide DPI arm only) on carbon footprint. RESULTS: As-needed budesonide/formoterol DPI was associated with 95.8% and 93.6% lower carbon footprint compared with as-needed salbutamol pMDI (least-squares mean 1.1 versus 26.2 kgCO2e; difference -25.0, 95% CI -29.7 to -20.4; p<0.001) and maintenance budesonide DPI plus as-needed salbutamol pMDI (least-squares mean 1.1 versus 17.3 kgCO2e; difference -16.2, 95% CI -20.9 to -11.6; p<0.001), respectively. There was no statistically significant evidence that treatment differences in carbon footprint depended on baseline symptom control or adherence in the maintenance budesonide DPI arm. CONCLUSIONS: The as-needed budesonide/formoterol DPI treatment option was associated with a markedly lower carbon footprint than as-needed salbutamol pMDI and maintenance budesonide DPI plus as-needed salbutamol pMDI.