Intravenous milrinone, a phosphodiesterase inhibitor and inodilator, has long been used in cardiac surgery to manage pulmonary hypertension (PH), especially during challenging separations from cardiopulmonary bypass (CPB). A notable disadvantage of intravenous milrinone is its potential to cause systemic hypotension. To mitigate this risk, inhalation has been proposed as an alternative method of administration. Pulmonary drug delivery offers benefits such as rapid absorption, high bioavailability, and increased local concentrations. Over the past decade, it has been hypothesized that inhaling milrinone before CPB could protect against the worsening of PH in cardiac surgery patients by reducing CPB-induced inflammation, preventing pulmonary endothelial dysfunction, and easing CPB separation. A multicenter randomized controlled trial confirmed the clinical efficacy of inhaled milrinone in lowering PH levels, though it did not show a reduction in the difficulty of CPB separation. Several factors, including suboptimal drug delivery, may account for these findings.

Nebulizers are commonly used for aerosol therapy in patients with pulmonary conditions. These devices work by converting liquid medications into fine, breathable droplets. There are three main types of nebulizers: jet, ultrasonic, and mesh. While ultrasonic and mesh nebulizers have been used in four clinical studies involving inhaled milrinone, jet nebulizers have typically been the standard for drug delivery in adult cardiac patients. Jet nebulizers operate by using a high-velocity jet of compressed gas (air or oxygen) to draw and shear the solution into aerosol droplets of various sizes. Ultrasonic nebulizers, on the other hand, use a high-frequency vibrating piezoelectric element to generate ultrasonic waves, breaking the solution into small aerosol droplets at the surface. Recent advancements in nebulization technology have led to the development of mesh nebulizers, which use a multi-aperture vibrating mesh (up to 10,000 apertures) to force the solution through holes, creating a high proportion of fine aerosol droplets. Over the past decade, mesh nebulizers have become increasingly popular, particularly for aerosol therapy in mechanically ventilated patients. These devices offer numerous advantages, including portability due to their compact design, no need for secondary airflow or liquid heating, and high efficiency in delivering drugs to the lungs with minimal waste.

This study on inhaled milrinone presents results from a randomized controlled pilot trial involving cardiac surgical patients undergoing CPB. The study had two main objectives: first, to assess the early plasma concentrations of milrinone in patients after both types of nebulization; and second, to determine whether systemic exposure in vivo was consistent with the inhaled dosing observed in vitro. It was hypothesized that milrinone delivered via mesh nebulization, with its smaller particle size, would result in higher early plasma levels compared to jet nebulization.

References

1Doolan, L. A., Jones, E. F., Kalman, J., Buxton, B. F. & Tonkin, A. M. A placebo-controlled trial verifying the efcacy of milrinone in weaning high-risk patients from cardiopulmonary bypass. J. Cardiothorac. Vasc. Anesth. 11, 37–41 (1997).

2. Solina, A. et al. A comparison of inhaled nitric oxide and milrinone for the treatment of pulmonary hypertension in adult cardiac surgery patients. J. Cardiothorac. Vasc. Anesth. 14, 12–17 (2000). 

3. Feneck, R. O., Sherry, K. M., Withington, P. S., Oduro-Dominah, A. & European Milrinone Multicenter Trial Group. Comparison of the hemodynamic efects of milrinone with dobutamine in patients afer cardiac surgery. J. Cardiothorac. Vasc. Anesth. 15, 306–315 (2001). 

4. Solina, A. R. et al. Dose response to nitric oxide in adult cardiac surgery patients. J. Clin. Anesth. 13, 281–286 (2001). 

5. Jaski, B. E., Fifer, M. A., Wright, R. F., Braunwald, E. & Colucci, W. S. Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside. J. Clin. Invest. 75, 643–649 (1985). 

6. Cufe, M. S. et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 287, 1541–1547 (2002). 

7. Couture, P., Denault, A. Y., Pellerin, M. & Tardif, J. C. Milrinone enhances systolic, but not diastolic function during coronary artery bypass grafing surgery. Can. J. Anesth. 54, 509–522 (2007).

Results showed that after mesh nebulization, the mean in vitro inhaled dose was nearly three times higher than after jet nebulization (46.4% vs. 16.6% for mesh and jet, respectively; mean difference, 29.8%; 95% CI, 14.1 to 45.5; P= 0.006). Consistent with this, early plasma concentrations in vivo were also 2–3 times higher after mesh nebulization (P= 0.002–0.005). Following both types of inhalation (jet or mesh nebulization), milrinone's early plasma concentrations remained within the therapeutic range, and no instances of systemic hypotension were reported in the patients.

Introduction

In China, the prevalence of paediatric asthma has increased over the past 20 years and is now approximately 3%. The long-term goals of asthma management according to the Global Initiative for Asthma (GINA) 2020 update are to improve and individualize the care of patients with asthma so that patients are able to achieve good control of symptoms and maintain normal activity levels, and have minimized risk of: asthma-related death, exacerbations, persistent airflow limitation and side effects.3The 2020 GINA guidelines suggest that poor adherence can be identified in clinical practice by empathic questioning that encourages open discussion, and acknowledges the probability of incomplete adherence. For optimal control of chronic diseases such as asthma, long-term adherence to treatment is required. If symptom control is poor and/or exacerbations persist despite 3 months of controller therapy, before considering a step-up of controller treatment, the relationship of symptoms to asthma should be confirmed, inhaler technique checked, good adherence confirmed or for children under 5-years old, an alternative treatment considered.

Methods

The CARE study was a 12-week, multicentre, prospective, observational study across 12 tertiary hospitals in China. Patients were aged 0–14 years, clinically diagnosed with asthma and prescribed home nebulizer inhaled corticosteroid (ICS) therapy for ⩾3 months. The primary endpoint was electronically monitored treatment adherence. Patients attended onsite visits at 0, 4, 8 and 12 weeks to assess asthma control, severity and treatment adherence (recorded by electronic monitoring devices and caregivers).

Results

The full analysis set included 510 patients. Median treatment adherence reported by electronic monitoring devices was 69.9%, and median caregiver-reported adherence was 77.9%. The proportion of patients with well-controlled asthma increased from 12.0% at baseline to 77.5% at visit 4. Increased time between asthma diagnosis and study enrolment was a significant predictor for better adherence [coefficient: 0.01, p = 0.0138; 95% confidence interval (CI): 0.00, 0.01] and asthma control (odds ratio = 1.001, p = 0.0498; 95% CI: 1.000, 1.002). Negative attitude to treatment by the caregiver was associated with poorer asthma control.

Discussion

To the best of our knowledge, this study is the first multicentre real-world study in China to record adherence to home nebulization of ICS treatment in asthmatic children using electronic monitoring devices.

In the present study, the median treatment adherence rate reported by portable home nebulizer devices was 69.9%, which compares favourably with many previous reports among children in other regions worldwide: the median electronically monitored adherence was 58.4% and 46%, respectively, in two studies in the USA, changing from 54% and 41% at month 4 to 47% and 31.5% at month 12 in patients with controlled and uncontrolled asthma, respectively, in a study from Brazil,16 and 49.5% in a study from The Netherlands. Results of the present study also compared favourably with other studies in China investigating treatment adherence in patients with asthma (adults or children). Furthermore, the World Health Organization reported that mean adherence was approximately 50% based on key studies in adults and children. Most of these studies reported adherence to metered-dose inhaler (MDI); comparatively, this results suggest that a home nebulizer device may facilitate better treatment adherence in paediatric patients.

Conclusion

Results of this study show that the rate of adherence to home nebulizer treatment in Chinese paediatric patients is good relative to prior reports in other countries and compared with other methods of ICS delivery. Furthermore, GINA-defined asthma control improved as the duration of treatment increased. We conclude that home nebulization of ICS is an effective long-term treatment method for paediatric patients with asthma.

Reference

1. Guo X, Li Z, Ling W, et al. Epidemiology of childhood asthma in mainland China (1988–2014): a meta-analysis. Allergy Asthma Proc 2018; 39: 15–29.

2. Hong J, Bao Y, Chen A, et al. Chinese guidelines for childhood asthma 2016: major updates, recommendations and key regional data. J Asthma 2018; 55: 1138–1146.

3. Global Initiative for Asthma. Global strategy for asthma management and prevention

4. Coutts JA, Gibson NA, Paton JY. Measuring compliance with inhaled medication in asthma. Arch Dis Child 1992; 67: 332–333.

5. Jentzsch NS, Camargos PA, Colosimo EA, et al. Monitoring adherence to beclomethasone in asthmatic children and adolescents through four different methods.

6. Milgrom H, Bender B, Ackerson L, et al. Noncompliance and treatment failure in children with asthma. J Allergy Clin Immunol

7. Boulet LP, Vervloet D, Magar Y, et al. Adherence: the goal to control asthma. 

November 20, 2024, marks the 23rd World COPD Day, with this year's theme, Know Your Lung Function. Lung function testing is a key method for diagnosing chronic obstructive pulmonary disease (COPD) and plays a crucial role in its early detection and prevention.

Chronic obstructive pulmonary disease (COPD) is a persistent lung condition resulting from lung damage. This damage leads to inflammation, or swelling and irritation, within the airways, restricting airflow in and out of the lungs—referred to as obstruction. Common symptoms include difficulty breathing, a daily mucus-producing cough, and a tight, whistling sound known as wheezing.

COPD is primarily caused by prolonged exposure to irritants such as smoke, fumes, dust, or chemicals, with cigarette smoke being the leading cause.

The two main forms of COPD are emphysema and chronic bronchitis, which often occur together but can vary in severity among individuals. Chronic bronchitis involves inflammation of the bronchi, the tubes that carry air into the lungs. This inflammation hinders airflow and results in excessive mucus production. In emphysema, the tiny air sacs in the lungs, called alveoli, are damaged, reducing their ability to transfer oxygen to the bloodstream.

Although COPD tends to worsen over time, it is manageable. With effective treatment, many people with COPD can control their symptoms, enhance their quality of life, and reduce the risk of complications like heart disease and lung cancer.

Feellife offers a comprehensive solution for respiratory health management through its innovative medical equipment. Its diverse range of core products—including pulmonary function meters, spirometry trainers, respiratory meters, and portable oxygen concentrators, each with unique functions and features—collectively supports the scientific prevention and treatment of COPD.

Management of acute exacerbations in emergency care primarily depends on nebulizers. Although jet nebulizers (JN) have been traditionally used, vibrating mesh nebulizers (VMN) are now being implemented.

A study compares aerosols generated by VMN with NIV and pulmonary deposition and distribution across regions of interest with administration of radiolabeled aerosol with jet nebulizer (JN) during NIV.

Methods

A crossover single dose study involving 9 stable subjects with moderate to severe COPD randomly allocated to receive aerosol administration by the VMN and the jet nebulizer operating with oxygen at 8 lpm during NIV. Radiolabeled bronchodilators (fill volume of 3 mL: 0.5 mL salbutamol 2.5 mg + 0.125 mL ipratropium 0.25 mg and physiologic saline up to 3 mL) were delivered until sputtering during NIV (pressures of 12 cmH2O and 5 cmH2O - inspiratory and expiratory, respectively) using an oro-nasal facemask. Radioactivity counts were performed using a gamma camera and regions of interest (ROIs) were delimited. Aerosol mass balance based on counts from the lungs, upper airways, stomach, nebulizer, circuit, inspiratory and expiratory filters, and mask were determined and expressed as a percentage of the total.

Results

Both inhaled and lung doses were greater with VMN (22.78 ± 3.38% and 12.05 ± 2.96%, respectively) than JN (12.51 ± 6.31% and 3.14 ± 1.71%; p = 0.008). Residual drug volume was lower in VMN than in JN (3.08 ± 1.3% versus 46.44 ± 5.83%, p = 0.001). Peripheral deposition of radioaerosol was significantly lower with JN than VMN.

Intragroup analysis of radioaerosol pulmonary index for ROI across vertical and horizontal gradients is shown in Table below

When analyzing intergroup deposition in different ROI across vertical and horizontal gradients, we found that NIV + VMN group had higher counts in comparison to NV + VMN group, as shown in Table below.

The percentage of inhaled mass was significantly higher in NIV + VMN group when compared to NIV + JN group (19.90 ± 3.18% versus 7.03 ± 2.97%, p = 0.008). VMN presented a lower residual volume (3.20 ± 1.33% versus 48.53 ± 6.40%, p = 0.008) and more radioaerosol deposited in the face mask and upper airways, in comparison to jet nebulizer during NIV. The JN demonstrated greater deposition in the expiratory filter than the VMN device. No differences were found regarding to mass balance found in the stomach, circuit and inspiratory filter for either group. Table represent the mass balance obtained in each compartment from both groups and mass balance of aerosol across pulmonary, extrathoracic and device compartments.

Conclusion

This study found more than 3-fold aerosolized particles from the total dose of 3 mL of solution charged into the VMN in comparison to JN. Further randomized controlled trials are necessary to evaluate clinical response to the increased level of aerosol deposition obtained from VMN and its impact to relieve respiratory discomfort and dynamic hyperinflation in COPD, as well as to develop recommendations for the use of this resource.

Reference

[1] Global Initiative for Chronic Obstructive Lung disease (GOLD), Global Strategy for Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease, (2013) available from: http://www.goldcopd.org/ , Accessed date: 3 April 2013.

[2] P. Haidl, S. Heindl, K. Siemon, M. Bernacka, R.M. Cloes, Inhalation device requirements for patients' inhalation maneuvers, Respir. Med. 118 (2016) 65–75.

[3] D. Hochrainer, H. Hӧlz, C. Kreher, L. Scaffidi, M. Spallek, H. Wachtel, Comparison of the aerosol velocity and spray duration of Respimat Soft Mist inhaler and pressurized metered dose inhalers, J. Aerosol Med. 18 (3) (2005 Fall) 173–282.

[4] V.G. Press, V.M. Arora, L.M. Shah, S.I. Lewis, K. Ivy, J. Charbeneau, et al., Misuse of respiratory inhalers in hospitalized patients with asthma or COPD, J. Gen. Intern.Med. 26 (6) (2011 Jun) 635–642.

[5] W. Vincken, P.R. Dekhuijzen, P. Barners, The ADMIT series – Issues in inhalation therapy. 4) How to choose inhalers devices for the treatment of COPD, Prim. Care Respir. J. 19 (1) (2010 Mar) 10–20.

[6] C. Leach, G.L. Colice, A. Luskin, Particle size of inhaler corticosteroids: Does it matter? Allergy Clin. Immunol. 124 (6 Suppl) (2009 Dec) S88–S93.

Budesonide is a medication used to manage and treat inflammatory diseases, mainly affecting the airways and gastrointestinal tract. It is in the corticosteroid class of medications. Clinicians are accustomed to adding budesonide suspension for inhalation to normal saline for nebulization. It is worth studying whether the particle size and zeta potential of the diluted budesonide suspension will affect the physical properties of the drug solution and whether it will affect the clinical efficacy.

A study analyzes the in vitro characteristics of inhaled budesonide suspension with different concentration gradient particle size and zeta potential, and compares the clinical efficacy, for providing the rational use of inhaled suspension in clinics with evidence-based medical evidence．

METHODS

According to the dilution times of budesonide suspension in clinical practice, the undiluted group, 1-fold dilution group, 2-fold dilution group, and 4-fold dilution group of budesonide suspension were set( n = 20). The changes of suspension particle size, zeta potential, and clinical efficacy of the four groups were compared．

RESULTS

The particle size of budesonide suspension with different concentration gradients changed significantly. There was a significant difference( P＜0．000 1) between the undiluted group ( 4 075±60) nm and the 1-fold dilution group ( 1 557±132) nm, and there was a significant difference ( P＜0．01) between the double dilution group ( 1 557±132) nm and the 2-fold dilution group ( 1 067±233) nm. At the same time, there was no significant difference between the 2-fold dilution group and the 4-fold dilution group. With the increase in dilution ratio, the zeta potential of budesonide suspension became extremely unstable, and the clinical efficacy gradually decreased．

Changes in particle size of budesonide suspensions at different concentration gradients

Changes in the Potential of Budesonide Suspensions at Different Concentration Gradients

CONCLUSION

The difference in concentration gradient can significantly affect the particle size and zeta potential of budesonide suspension, which may cause the decrease in titer.In order to ensure clinical efficacy, the diluted solvent of budesonide suspension for inhalation should not exceed 1 time of the original solution.

Reference

[1] Feng Q，Xiao H，Zheng C，et al．Immunosuppressive triangle depletion through the combination punches strategy for enhanced immunotherapy．Applied Materials Today，2022，26: 1013-1015．

[2] Chen C M，Chang C H，Chao C H，et al．Biophysical and chemical stability of surfactant /budesonide and the pulmonary distribution following intra-tracheal administration［J］．Drug Delivery，2019，26( 1) :604-611．

[3]Wang H M．Analysis of ultrasonic atomized inhalation of antibiotics in infant pneumonia treatment.［J］．Pak J Pharm Sci，2018，31:1653-1657．

Pediatric bronchopneumonia is a common clinical respiratory disease in pediatrics and is the leading cause of death in children<5 years of age. The clinical course of bronchopneumonia is influenced by a number of factors, including the patient's age, condition, immunity, and various medical interventions. In addition to infection control, anti-inflammatory measures such as cough suppression and sputum reduction should not be neglected. At present, the clinical treatment of pediatric bronchopneumonia is mainly the application of anti-infective drugs for antibacterial and antiviral therapy, but the simple application of anti-infective drug therapy is not ideal.

Ambroxol hydrochloride is an expectorant, on the one hand, it can dilute sputum, strengthen the ciliary function of columnar epithelial cells, which is conducive to sputum discharge; on the other hand, it can promote the synthesis and secretion of alveolar surface-active substances, and reduce the surface tension; in addition, it has an antioxidant effect as well as reduces the release of inflammatory mediators, attenuates bronchial hyperresponsiveness and reduces inflammatory reactions in lung tissues. Other studies have shown that Ambroxol hydrochloride increases the concentration of antimicrobial drugs in the airways, enhances their anti-infective capacity, and strengthens the ability of macrophages to phagocytose and kill bacteria. Therefore, Ambroxol Hydrochloride is widely used in the clinical treatment of respiratory diseases to stop cough and expectorant, especially nebulized inhalation can directly enter the lesion to play a rapid role. Budesonide is a new type of adrenocorticotropic hormone, with high glucocorticoid receptor binding capacity, strong anti-inflammatory effect, and a small dose can achieve significant therapeutic effect.

The application of budesonide in the treatment of pneumonia is mainly related to the following effects:

1.inhibition of the synthesis and release of inflammatory cytokines and inflammatory mediators.

2. Repairing the airway and inhibiting airway hyperreactivity.

3. Inhibiting the release of mucus glycoproteins in the airways and secretion from the airway epithelial mucosa. 

The systemic adverse effects of glucocorticoids limit the clinical use of these drugs. However, nebulized inhalation budesonide dose is small, the drug is mainly absorbed by the lungs, high deposition rate in the lungs, long retention time, strong local anti-inflammatory effect, and strong first-pass metabolism of budesonide swallowed through the mouth (90%), so there are fewer adverse reactions at therapeutic doses, and the safety is higher.

A study showed that budesonide combined with aminobromosol hydrochloride nebulized inhalation treatment of pediatric bronchopneumonia was superior to nebulized inhalation of aminobromosol hydrochloride alone, both in terms of the degree of symptom elimination and the duration of symptoms. Therefore, budesonide combined with ambroxol hydrochloride nebulized inhalation is effective in improving the symptoms of pediatric bronchopneumonia, and is worthy of clinical recommendation.

Invasive mechanically assisted ventilation is a common treatment for intensive care unit (ICU) patients. Because of a variety of factors, including an aging population, the number of patients who receive mechanical ventilation is increasing. Each year, one-third of patients require mechanical ventilation (MV) for more than 48 h, and many patients require aerosol therapy during the MV. Aerosol therapy is a safe and convenient method of treatment and commonly used in patients with invasive MV in the ICU, especially for patients with asthma and chronic obstructive pulmonary disease. The three most commonly used aerosolizing drugs are bronchodilators, corticosteroids, and antibiotics. However, the effect of aerosolized inhalation is reduced due to the establishment of an artificial airway in a tracheal intubated patient.  In patients with artificial airways, aerosol transmission was only one-sixth of what it was in patients without artificial airways. Over the past 25 years, with the development of aerosol equipment and operation technology, the aerosol delivery to invasive MV patients has almost been matched and even exceeded that reported in patients with nonartificial airways.

Many factors may affect the efficacious delivery of aerosols to the lungs. These factors are associated with patients, drugs, devices, artificial airways, ventilator settings, and ventilator circuits. The position of nebulizers placed by ICU nurses is another important factor. In clinical practice, the most common nebulizer position was between the tracheal tube and the Y-piece (41~46%) or after Y-piece (39~41%), respectively. Many in vitro tests showed that, when the nebulizer was placed after Y-piece or between the ventilator inlet and heated humidifier, drug delivery to the lungs was the largest.

A study indicated that when the nebulizer was placed 80 cm away from the Y-piece, the salbutamol concentrations were the highest in both serum and urine, whilst the lowest drug concentration was found when the nebulizer was located between the tracheal tube and Y-piece.

                                            Different positions of the nebulizer

Most patients with invasive MV will receive aerosol therapy every day, and ICU nurses play a crucial role during the implementation of this therapy. However, some studies showed marked discrepancies in the nebulizer operation between trial and clinical practice paradigms. This was particularly true when it came to the optimal nebulizer position. Thus, targeted atomization education or training is necessary for all ICU nurses. Increasing the awareness of ICU nurses to different nebulizer positions will likely affect aerosol delivery and help determine which position is best for patients. Moreover, standards or guidelines for aerosol therapy should focus on standardizing the atomization operation and developing measures to deal with potential hazards. Furthermore, targeted atomization educational programs should be implemented through departments or hospital education and academic conferences. Finally, future atomization studies should attempt to mirror clinical practice settings and be easy to operate. Even though the study data shows that changing the ventilator parameters during the atomization operation may be more effective, this may be very difficult to implement in clinical practice.

Reference

[1] Tobin M., Manthous C. Mechanical ventilation. American Journal of Respiratory and Critical Care Medicine.

[2] Luyt C. E., Hékimian G., Bréchot N., Chastre J. Aerosol therapy for pneumonia in the intensive care unit. Clinics in Chest Medicine.

[3] Pleasants R. A., Hess D. R. Aerosol delivery devices for obstructive lung diseases. Respiratory Care.

[4] Wen M., Zheng F. M., Li G. X., Xu J. Q. Observation on the airway effect of nebulizer at different positions for patients undergoing mechanical ventilation. Chinese General Nursing.